WRN inhibitor compound and use thereof

Abstract

Provided in the present disclosure are a WRN inhibitor compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use thereof as a WRN inhibitor in the prevention or treatment of related diseases.

Description

WRN inhibitor compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of the following Chinese patent applications filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202410231931.6 filed on February 29, 2024; Chinese Patent Application No. 202410332343.1 filed on March 21, 2024; Chinese Patent Application No. 202410513176.0 filed on April 26, 2024; Chinese Patent Application No. 202410651779.7 filed on May 24, 2024; Chinese Patent Application No. 202410847628.9 filed on June 27, 2024; Chinese Patent Application No. 202410998367.0 filed on July 24, 2024; and Chinese Patent Application No. 202411615991.4 filed on November 13, 2024. The contents of the above patent application disclosures are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to WRN inhibitor compounds or pharmaceutically acceptable salts thereof, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof as WRN inhibitors in preventing or treating related diseases. Background Art

[0004] Helicases are enzymes that unwind double-stranded nucleotides. They utilize the energy released during the hydrolysis of nucleoside triphosphates to move along nucleic acid chains, thereby unwinding and separating the double-stranded nucleic acids. As a representative of DNA helicases, the RecQ helicase family plays a significant role in maintaining chromosomal genome and telomere stability. During DNA replication, they catalyze the unwinding of double-stranded DNA, completing DNA repair and thus maintaining genomic integrity.

[0005] RecQ family helicases are highly conserved throughout evolution. Their functions are involved in various DNA metabolic processes and are crucial for maintaining genomic stability. Loss of function in five human RecQ family helicases, BLM, WRN, and RecQ4, leads to BLM syndrome, WRN syndrome, and Rothmund-Thomson syndrome, respectively. These diseases all manifest at the molecular level as high genomic instability, chromosomal abnormalities, and sensitivity to DNA damage.

[0006] WRN and RecQ1 are the two most representative RecQ helicases. WRN includes an exonuclease domain in addition to its unwinding domain. Werner syndrome (WS) is an autosomal recessive disorder characterized by accelerated clinical aging and a lifespan of less than 50 years. The WS helicase nuclease (WRN) participates in numerous important pathways, including DNA replication, recombination, and repair. WRN unwinds non-canonical secondary DNA structures encountered during replication and recombination, and mutations in WRN can cause chromosomal instability disorders such as Werner syndrome. Normally, WRN depletion causes DNA double-strand breaks in MSI cells, leading to cell cycle arrest and / or apoptosis. Studies have demonstrated a strong synthetic lethality relationship between WRN helicase and microsatellite instability-high (MSI-H) cancers. WRN forms a synthetic lethal relationship with the DNA mismatch repair protein MutL homolog 1 (MLH1), and loss of MLH1 is associated with microsatellite instability (MSI).

[0007] Microsatellites are simple repeat sequences of less than 10 nucleotides in the genome. DNA mismatch repair (MMR) defects, triggered by gene mutations or promoter hypermethylation, can lead to hypermutation of nucleotide repeat regions (microsatellites), a phenomenon known as microsatellite instability (MSI). MSI contributes to the pathogenesis of various cancers, including colon (15%), gastric (22%), endometrial (20%-30%), and ovarian (12%) cancers, 45%-60% of which are unresponsive to immune checkpoint blockade. Therefore, new treatment approaches are needed for MSI tumors. In two studies of genome-wide gene inactivation using CRISPR or RNA interference, WRN was identified as the primary dependency of MSI-H cells, and this dependency was associated with unwinding activity, but not with WRN's nuclease function. These findings, coupled with the fact that WRN silencing is well tolerated in microsatellite-stable (MSS) cancer cells, demonstrate that WRN is a potential specific target for the treatment of MSI tumors.

[0008] Given the huge unmet clinical needs, the development of small molecule inhibitors targeting WRN has broad application prospects. Summary of the Invention

[0009] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010] in,

[0011] X 2 and X 4 One is N and the other is C;

[0012] R 1 is selected from 4-12 membered heterocyclylene, 5-10 membered heteroarylene or C6-C 14 Arylene, the 4-12 membered heterocyclylene, 5-10 membered heteroarylene or C6-C 14 The arylene group is optionally replaced by R 6’ replace;

[0013] R 6’ Selected from halogen, hydroxyl or C1-C6 alkyl;

[0014] R 6 Selected from hydrogen, hydroxy, amino, halogen, oxo, cyano, C(O)C3-C 10 Cycloalkyl, C(O)C1-C 10 Alkyl, 5-10 membered heteroaryl, C(O)4-12 membered heterocyclic group, C(O)NHC1-C6 alkyl, C(O)OC3-C 10 Cycloalkyl, C(O)OC1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), C1-C 10 Alkyl, C1-C 10 Alkoxy, -O-C3-C 10 Cycloalkyl, -S-C3-C 10 Cycloalkyl, -O-4-12 membered heterocyclic group, -S-4-12 membered heterocyclic group, -S-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -S(O)-C3-C 10 Cycloalkyl, -S(O)-C1-C 10 Alkyl, -S(O)2-C3-C 10 Cycloalkyl, -S(O)2-C1-C 10 Alkyl, 4-12 membered heterocyclic group, -N=S(O)(C1-C6 alkyl)2, -S(O)(NH)-C3-C 10 Cycloalkyl, -S(O)(NC1-C6 alkyl)-C3-C 10 Cycloalkyl, -S(O)(NH)-C1-C 10 Alkyl or -S(O)(NC1-C6 alkyl)-C1-C 10 Alkyl, the C(O)C3-C 10 Cycloalkyl, C(O)C1-C 10 Alkyl, 5-10 membered heteroaryl, C(O)4-12 membered heterocyclic group, C(O)NHC1-C6 alkyl, C(O)OC3-C 10 Cycloalkyl, C(O)OC1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), C1-C 10 Alkyl, C1-C10 Alkoxy, -O-C3-C 10 Cycloalkyl, -S-C3-C 10 Cycloalkyl, -O-4-12 membered heterocyclic group, -S-4-12 membered heterocyclic group, -S-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -S(O)-C3-C 10 Cycloalkyl, -S(O)-C1-C 10 Alkyl, -S(O)2-C3-C 10 Cycloalkyl, -S(O)2-C1-C 10 Alkyl, 4-12 membered heterocyclic group, -N=S(O)(C1-C6 alkyl)2, -S(O)(NH)-C3-C 10 Cycloalkyl, -S(O)(NC1-C6 alkyl)-C3-C 10 Cycloalkyl, -S(O)(NH)-C1-C 10 Alkyl or -S(O)(NC1-C6 alkyl)-C1-C 10 The alkyl group is optionally replaced by R 6a replace;

[0015] R 6a Selected from oxo, halogen, cyano, amino, OH, C1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), NH(C3-C6 cycloalkyl), N(C1-C6 alkyl)(C3-C6 cycloalkyl), C1-C6 alkoxy, 4-12 membered heterocyclyl, C3-C 10 Cycloalkyl or COOH, the C1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), NH(C3-C6 cycloalkyl), N(C1-C6 alkyl)(C3-C6 cycloalkyl), C1-C6 alkoxy, 4-12 membered heterocyclyl or C3-C 10 The cycloalkyl group is optionally replaced by R 6b replace;

[0016] R 6b is selected from deuterium, halogen, oxo, hydroxy, amino, cyano, N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), C1-C6 alkyl or C1-C6 alkoxy, wherein the N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 6c replace;

[0017] R 6c is selected from halogen, hydroxy, amino or cyano;

[0018] R 2 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally replaced by R2a replace;

[0019] R 2a is selected from halogen, C1-C6 alkyl, SF5 or C(O)H, wherein the C1-C6 alkyl is optionally substituted with halogen;

[0020] R 3 is selected from C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally replaced by R 3a replace;

[0021] R 3a Selected from halogen, hydroxy or C1-C4 alkyl;

[0022] e is a single bond or a double bond,

[0023] When e is a single bond, Y is N, R 52 and R 53 are each independently selected from hydrogen, halogen or C1-C3 alkyl, or R 52 and R 53 and the atoms to which they are connected together form a C3-C6 cycloalkyl group; or Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C6 cycloalkyl group;

[0024] When e is a double bond, Y is C, R 52 and R 53 Each is independently selected from hydrogen, halogen or C1-C3 alkyl;

[0025] R 4 Selected from

[0026] R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 Each is independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy optionally substituted by halogen;

[0027] Provided that the compound is not:

[0028] In some embodiments, X 2 C, X 4 is N.

[0029] In some embodiments, X 2 N, X 4is C. In some embodiments, R 1 Selected from 4-12 membered heterocyclylene or C6-C 14 Arylene, the 4-12 membered heterocyclic group or C6-C 14 The arylene group is optionally replaced by R 6’ replace.

[0030] In some embodiments, R 1 is selected from 4-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene, wherein the 4-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene is optionally replaced by R 6’ replace.

[0031] In some embodiments, R 1 is selected from 6-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene, wherein the 6-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene is optionally replaced by R 6’ replace.

[0032] In some embodiments, R 1 Selected from phenylene, pyridylene, thiazolylene, morpholinylene, dihydropyranylene, tetrahydropyridylene, The phenylene, pyridylene, thiazolyl, morpholinyl, dihydropyranyl, tetrahydropyridyl, Optional R 6’ Substituted, where R 1 The “——” in the text indicates that the 2 connect.

[0033] In some embodiments, R 1 is selected from 4-10 membered heterocyclylene or phenylene, wherein the 4-10 membered heterocyclylene or phenylene is optionally replaced by R 6’ replace.

[0034] In some embodiments, R 1 Selected from 9-10 membered heterocyclylene or phenylene, said 9-10 membered heterocyclylene or phenylene optionally replaced by R 6’ Substituted, where R 1 The “——” in the text indicates that the 2 connect.

[0035] In some embodiments, R 1 is selected from 9-10 membered heterocyclylene or phenylene, wherein the 9-10 membered heterocyclylene or phenylene is optionally replaced by R 6’ replace.

[0036] In some embodiments, R 1is selected from phenylene, the phenylene being optionally replaced by R 6’ replace.

[0037] In some embodiments, R 6 is selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl, wherein the C1-C8 alkyl, C1-C8 alkoxy, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl is optionally replaced by R 6a replace.

[0038] In some embodiments, R 6 is selected from hydrogen, hydroxy, methoxy, methyl, isopropyl, azetidinyl, cyclobutyl, cyclopropyl or O-azetidinyl, wherein the methoxy, methyl, isopropyl, azetidinyl, cyclobutyl, cyclopropyl or O-azetidinyl is optionally replaced by R 6a replace.

[0039] In some embodiments, R 6 is selected from hydrogen, hydroxy, C1-C8 alkyl, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl, wherein the C1-C8 alkyl, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl is optionally replaced by R 6a In some embodiments, R 6 is selected from hydroxy, C1-C8 alkyl, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl, wherein the -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl is optionally replaced by R 6a Substituted, the C1-C8 alkyl group is replaced by R 6a Replace, and when R 6 Selected from R 6a When the C1-C8 alkyl group is substituted, R 6a Selected from hydroxyl, cyano, and optionally R 6b Substituted C3-C6 cycloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C6 cycloalkyl), N(C1-C6 alkyl)(C3-C6 cycloalkyl), 4-12 membered heterocyclyl or C1-C6 alkoxy.

[0040] In some embodiments, R 6 is selected from hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -O-4-membered heterocyclic group, C3-C4 cycloalkyl or 4-membered heterocyclic group, wherein the C1-C3 alkyl, C1-C3 alkoxy, -O-4-membered heterocyclic group, C3-C4 cycloalkyl or 4-membered heterocyclic group is optionally replaced by R 6a replace.

[0041] In some embodiments, R 6 is selected from hydroxy, C1-C3 alkyl, -O-4 membered heterocyclic group, C3-C4 cycloalkyl or 4 membered heterocyclic group, wherein the -O-4 membered heterocyclic group, C3-C4 cycloalkyl or 4 membered heterocyclic group is optionally replaced by R 6a Substituted, the C1-C3 alkyl group is replaced by R 6a Replace, and when R 6 Selected from R 6a When the C1-C3 alkyl group is substituted, R 6a Selected from R 6b Substituted N(C1-C3 alkyl)2- or 4-7-membered heterocyclic group.

[0042] In some embodiments, R 6 is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is replaced by R 6a Replacement, R 6a Selected from R 6b Substituted N(C1-C3 alkyl)2- or 4-7-membered heterocyclic group.

[0043] In some embodiments, R 6 is selected from methyl, said methyl being R 6a Replacement, R 6a Selected from R 6b Substituted N(C1-C3 alkyl)2- or 4-7-membered heterocyclic group.

[0044] In some embodiments, R 6 is selected from methyl, said methyl being R 6a Replacement, R 6a Selected from R 6b Substituted N(C1-C3 alkyl)2- or 4-7-membered heterocyclic group, and when R 6a Selected from R 6b In the case of a substituted 4- to 7-membered heterocyclic group, the ring atom to which the methyl group is attached is a heteroatom.

[0045] In some embodiments, R 6 is selected from methyl, said methyl being R 6a Replacement, R 6a Selected from R 6b Substituted N(C1-C3 alkyl)2- or 4-7-membered heterocyclic group, and when R 6a Selected from R 6b In the case of a substituted 4- to 7-membered heterocyclic group, the ring atom to which the methyl group is attached is a nitrogen atom.

[0046] In some embodiments, R 6ais selected from halogen, C1-C6 alkyl, N (C1-C6 alkyl) 2 or 4-12 membered heterocyclic group, wherein the C1-C6 alkyl, N (C1-C6 alkyl) 2 or 4-12 membered heterocyclic group is optionally replaced by R 6b replace.

[0047] In some embodiments, R 6a is selected from halogen, C1-C3 alkyl, N (C1-C3 alkyl) 2 or 4-7 membered heterocyclic group, wherein the C1-C3 alkyl, N (C1-C3 alkyl) 2 or 4-7 membered heterocyclic group is optionally replaced by R 6b replace.

[0048] In some embodiments, R 6a Selected from fluorine, N(CH3)2, N(CH3)(CH(CH3)2), ethyl, azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, The N(CH3)2, N(CH3)(CH(CH3)2), ethyl, azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, Optional R 6b replace.

[0049] In some embodiments, R 6b is selected from halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl or C1-C6 alkoxy.

[0050] In some embodiments, R 6b is selected from deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 6c replace.

[0051] In some embodiments, R 6b is selected from halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0052] In some embodiments, R 6b is selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0053] In some embodiments, R 6c In some embodiments, R 6 Selected from hydrogen, methoxy, methyl, isopropyl, CHF2, cyclopropyl,

[0054] In some embodiments, R 6 Selected from

[0055] In some embodiments, R 6 Selected from

[0056] In some embodiments, R 6’ is selected from halogen or hydroxy.

[0057] In some embodiments, R 6’ Selected from halogen, hydroxyl or C1-C3 alkyl.

[0058] In some embodiments, R 6’ is selected from fluorine, chlorine, hydroxy or methyl.

[0059] In some embodiments, R 6’ Selected from fluorine or hydroxy.

[0060] In some embodiments, R 6’ Selected from halogen.

[0061] In some embodiments, R 6’ Selected from fluorine.

[0062] In some embodiments, Selected from

[0063] In some embodiments, R 2 is selected from phenyl or 8-10 membered heteroaryl, wherein the phenyl or 8-10 membered heteroaryl is optionally replaced by R 2a replace.

[0064] In some embodiments, R 2 is selected from phenyl or 9-membered heteroaryl, wherein the phenyl or 9-membered heteroaryl is optionally replaced by R 2a replace.

[0065] In some embodiments, R 2 is selected from phenyl or indolyl, wherein the phenyl or indolyl is optionally replaced by R 2a replace.

[0066] In some embodiments, R 2 is selected from 8-10 membered heteroaryl, wherein the 8-10 membered heteroaryl is optionally replaced by R 2a replace.

[0067] In some embodiments, R 2 is selected from 9-membered heteroaryl, wherein the 9-membered heteroaryl is optionally replaced by R 2a replace.

[0068] In some embodiments, R 2a is selected from halogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by halogen.

[0069] In some embodiments, R 2ais selected from halogen or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by halogen.

[0070] In some embodiments, R 2a is selected from fluorine, chlorine, bromine or methyl, said methyl being optionally substituted by fluorine.

[0071] In some embodiments, R 2 Selected from

[0072] In some embodiments, R 3 Selected from C1-C4 alkyl.

[0073] In some embodiments, R 3 is selected from C1-C4 alkyl or C3-C4 cycloalkyl, wherein the C3-C4 cycloalkyl is optionally replaced by R 3a replace.

[0074] In some embodiments, R 3 is selected from ethyl, cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl is optionally replaced by R 3a replace.

[0075] In some embodiments, R 3 Selected from ethyl.

[0076] In some embodiments, R 3a Selected from halogen or C1-C4 alkyl.

[0077] In some embodiments, R 3a Selected from fluorine or methyl.

[0078] In some embodiments, R 3 Selected from ethyl, cyclopropyl,

[0079] In some embodiments, e is a single bond or a double bond,

[0080] When e is a single bond, R 53 It is H, Y, it is N, R 52 is hydrogen; or Y is CR 51 , R 51 and R 52 and the atoms to which they are attached together form a C3-C6 cycloalkyl group;

[0081] When e is a double bond, R 53 is H, Y is C, R 52 For hydrogen.

[0082] In some embodiments, e is a single bond or a double bond,

[0083] When e is a single bond, Y is N, R 52 and R 53 are each independently selected from hydrogen or C1-C3 alkyl, or R 52 and R 53 and the atoms to which they are connected together form a C3-C4 cycloalkyl group; or Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C4 cycloalkyl group;

[0084] When e is a double bond, Y is C, R 52 and R 53 Each is independently selected from hydrogen, halogen or C1-C3 alkyl.

[0085] In some embodiments, e is a single bond or a double bond,

[0086] When e is a single bond, Y is N, R 53 is H or methyl, R 52 is hydrogen, or R 52 and R 53 and the atoms to which they are attached together form a cyclobutyl group; or Y is CR 51 , R 51 and R 52 and the atoms to which they are attached together form a cyclopropyl group;

[0087] When e is a double bond, Y is C, R 53 is H or methyl, R 52 is hydrogen, fluorine or methyl.

[0088] In some embodiments, e is a single bond or a double bond,

[0089] When e is a single bond, Y is N, R 52 is hydrogen; or Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C4 cycloalkyl group;

[0090] When e is a double bond, Y is C, R 52 For hydrogen.

[0091] In some embodiments, e is a single bond or a double bond,

[0092] When e is a single bond, Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C4 cycloalkyl group;

[0093] When e is a double bond, Y is C, R 52 and R 53Each is independently selected from hydrogen, halogen or C1-C3 alkyl.

[0094] In some embodiments, R 53 It's hydrogen.

[0095] In some embodiments, e is a single bond or a double bond,

[0096] When e is a single bond, Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C4 cycloalkyl group;

[0097] When e is a double bond, Y is C, R 52 For hydrogen.

[0098] In some embodiments, e is a single bond, Y is CR 51 , R 51 and R 52 and the atoms to which it is attached together form a cyclopropyl group.

[0099] In some embodiments, Selected from

[0100] In some embodiments, Selected from

[0101] In some embodiments, Selected from

[0102] In some embodiments, R 4 Selected from

[0103] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 Each is independently selected from hydrogen or C1-C4 alkyl.

[0104] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 are each independently selected from hydrogen or methyl.

[0105] In some embodiments, R 4 Selected from

[0106] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (I-1):

[0107] Among them, e, X 2 、X 4 、R 1 、R 2 、R 3 、R 4 、R 52 、R 6 or Y is as defined for the compound of formula (I).

[0108] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (II):

[0109] Among them, e, R 1 、R 2 、R 3 、R 4 、R 52 、R 6 or Y is as defined for the compound of formula (I).

[0110] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (II-1):

[0111] Among them, e, R 1 、R 2 、R 3 、R 4 、R 52 、R 53 、R 6 or Y is as defined for the compound of formula (I).

[0112] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (II-2):

[0113] Among them, e, R 2 、R 3 、R 4 、R 52 、R 53 、R 6 、R 6’ or Y is as defined for the compound of formula (I), and m is selected from 0, 1, 2, 3 or 4.

[0114] In some embodiments, m is selected from 0 or 1.

[0115] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (III):

[0116] Among them, X 2 、X 4 、R 1 、R 2 、R 3 、R 4 、R 52 or R 6 As defined for the compounds of formula (I).

[0117] In some embodiments, the compounds of formula (I) of the present disclosure are selected from compounds of formula (IV):

[0118] Among them, R 1 、R 2 、R 3 、R 4 or R 6 As defined for the compounds of formula (I).

[0119] In some embodiments, the compounds of formula (I) of the present disclosure are selected from the following compounds:

[0120] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0121] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for inhibiting WRN.

[0122] In some embodiments, the use is for treating cancer.

[0123] In another aspect, the present disclosure provides a method for inhibiting WRN, comprising the step of contacting a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof with WRN.

[0124] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a WRN inhibitor.

[0125] In another aspect, the present disclosure provides a method for treating a disease mediated by WRN helicase in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0126] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease mediated by WRN helicase.

[0127] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by WRN helicase.

[0128] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by WRN helicase.

[0129] In some embodiments, the WRN helicase-mediated disease is selected from cancer or Werner syndrome.

[0130] In some embodiments, the cancer is colon cancer.

[0131] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, particularly for use in treating a condition or disease that is treatable by WRN inhibition.

[0132] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer.

[0133] In another aspect, the present disclosure provides a method of modulating WRN activity in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0134] In another aspect, the present disclosure provides a method of inhibiting WRN in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0135] In another aspect, the present disclosure provides a method of treating a condition or disease treatable by WRN inhibition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0136] In another aspect, the present disclosure provides a method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0137] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament.

[0138] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer.

[0139] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease that can be treated by WRN inhibition.

[0140] Definitions and Explanations of Terms

[0141] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0142] In this article Indicates the attachment site.

[0143] In this disclosure, "*" or "#" indicates that the atom it identifies is a linking site, such as a linking group. It indicates that the N atom in the linking group is the linking site.

[0144] In the ring Indicates that the corresponding ring is an aromatic ring. Structural unit It can be understood as an aromatic ring having a cyclic conjugated system.

[0145] In this paper, the bonds depicted by solid and dashed lines represents a single bond or a double bond. For example, the structural unit Include

[0146] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0147] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0148] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0149] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0150] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (ie, =O), it means that two hydrogen atoms are replaced.

[0151] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0152] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0153] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0154] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0155] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0156] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0157] In this article, C m -C nIt means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0158] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 "Alkyl" may include "C1-C8 alkyl", "C1-C6 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C3 alkyl". The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0159] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 The term "cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C8 cycloalkyl" and "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0160] The term "heterocyclyl" refers to a fully saturated or partially saturated monocyclic, fused, spiro or bridged ring group, which contains 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-18 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms, and contains 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms in its ring atoms. The term "4-12 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-described heteroatoms. "4-10 membered heterocyclyl" includes "4-7 membered heterocyclyl," wherein specific examples of 4-membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group or a heteroaromatic ring-fused ring group of the above-mentioned 4-7-membered heterocyclic group, specific examples of which include but are not limited to dihydroisoquinolinyl. The heterocyclic group may also be a tricyclic group. The “4-10 membered heterocyclyl” may include the ranges of “5-10 membered heterocyclyl”, “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, and the like, and the “4-7 membered heterocyclyl” may further include the ranges of “4-6 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, and the like.Although some bicyclic heterocyclic groups disclosed herein partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0161] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0162] The term "phenylene" refers to a divalent group derived from a "phenyl" group.

[0163] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. “5-10 membered heteroaryl” includes “5-6 membered heteroaryl”. The term “5-6 membered heteroaryl” refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.

[0164] The term "cycloalkylene" refers to a divalent group derived from a "cycloalkyl" group as defined herein.

[0165] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include, but are not limited to, trifluoromethanesulfonate, chlorine, bromine, iodine, sulfonate (e.g., methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate), or acyloxy (e.g., acetoxy, trifluoroacetoxy), etc.

[0166] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0167] The term "hydroxy" refers to an -OH group.

[0168] The term "amino" refers to a -NH2 group.

[0169] The term "C(O)" refers to a -C(=O) group.

[0170] The term "WRN inhibitor" or "WRN helicase inhibitor" refers to a compound that inhibits Werner Syndrome RecQ DNA helicase (WRN). The term "WRN" refers to the protein of Werner Syndrome RecQ DNA helicase. The term "WRN" includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. "Diseases or conditions mediated by WRN" include diseases or conditions that are treated by WRN inhibition, such as cancer.

[0171] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0172] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0173] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0174] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0175] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0176] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0177] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0178] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0179] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0180] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0181] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0182] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0183] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0184] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0185] In all methods of administration of the compounds of formula I described herein, the daily dosage may be from 0.01 mg / kg to 100 mg / kg body weight, in single or divided doses.

[0186] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0187] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0188] This application uses the following abbreviations: DETAILED DESCRIPTION

[0189] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0190] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0191] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0192] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0193] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0194] Intermediate Int-1: Synthesis of 2-(2-bromo-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 (Intermediate Int-1)

[0195] Step 1: Synthesis of intermediate Int1-2

[0196] Intermediate Int1-1 (1.0 g) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (2.5 mL) was added. The reaction was allowed to react at 20°C for 15 hours, and the reaction was complete. Water (30 mL) was added, and the pH was adjusted to 12-13 with 3N aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane (100 mL x 2). The organic phase was washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 690.8 mg of intermediate Int1-2.

[0197] Step 2: Synthesis of intermediate Int-1

[0198] Intermediate Int1-2 (680.8 mg) was dissolved in N,N-dimethylformamide (10 mL), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (224.2 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (348.3 mg), and 1-hydroxybenzotriazole (33.1 mg) were added. The mixture was reacted at 20°C for 2 hours, and the reaction was completed. Water (30 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted and separated. The organic phase was washed once with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain 445.5 mg of intermediate Int-1.

[0199] LC-MS (ESI): m / z = 698.0 [M+H] +

[0200] Intermediate 14-1: Synthesis of 2-(6-bromo-5-ethyl-7-oxo-2-phenyl-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Intermediate 14-1)

[0201] Step 1: Synthesis of compound Int2-3

[0202] Compound Int2-2 (2.2 g, 23.4 mmol) was dissolved in a 6 M aqueous hydrochloric acid solution (12.8 mL). A solution of sodium nitrite (1.5 g, 21.3 mmol) dissolved in water (16.0 mL) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Urea (127.8 mg, 2.1 mmol) was then added to consume the excess sodium nitrite. The above solution was then added to a solution of compound Int2-1 (4.0 g, 21.3 mmol) dissolved in water (120.0 mL) and allowed to react at room temperature for 1.5 h. A solution of sodium acetate (6.3 g, 76.6 mmol) in water (120 mL) was then added dropwise, followed by stirring at room temperature for 12 h. The reaction was complete. The reaction mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 6.0 g of crude compound Int2-3.

[0203] Step 2: Synthesis of compound Int2-4

[0204] Int2-3 (5.0 g, 15.2 mmol) was dissolved in water (20.0 mL) and pyridine (40.0 mL), and anhydrous copper sulfate (12.1 g, 76.1 mmol) was added. The reaction was then allowed to react at 100°C for 1 h. The reaction mixture was diluted with water (200.0 mL) and extracted with ethyl acetate (100.0 mL x 3). The organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain 1.3 g of compound Int2-4.

[0205] Step 3: Synthesis of compound Int2-5

[0206] Compound Int2-4 (1.1 g, 3.79 mmol) was dissolved in methanol (15.0 mL), followed by the addition of sodium methoxide solution (5.4 M, 2.8 mL). The mixture was then allowed to react at 80°C for 4 h, until the reaction was complete. The reaction solution was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to afford 500 mg of compound Int2-5.

[0207] Step 4: Synthesis of compound Int2-6

[0208] Compound Int2-5 (380.0 mg, 1.6 mmol) was dissolved in acetonitrile (3.8 mL). tert-Butyl nitrite (324.8 mg, 3.2 mmol) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 40 min. Cuprous bromide (903.8 mg, 6.3 mmol) was then added, and the mixture was allowed to react at 80°C for 2 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to afford 130 mg of compound Int2-6.

[0209] Step 5: Synthesis of compound Int2-7

[0210] Compound Int2-6 (100.0 mg, 327.7 μmol) was dissolved in tetrahydrofuran (2.0 mL), followed by the addition of ferric acetylacetonate (5.8 mg, 16.4 μmol). Ethylmagnesium bromide (1 M, 983.2 μL) was added dropwise under nitrogen at -20°C. The mixture was allowed to react for 30 min at -20°C and then for 30 min at room temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to afford 65.0 mg of compound Int2-7.

[0211] Step 6: Synthesis of compound Int2-8

[0212] Compound Int2-7 (60.0 mg, 235.9 μmol) was dissolved in hydrogen bromide and acetic acid solution (2.0 mL) and reacted at 80°C for 12 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was dried, concentrated, and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain 35.0 mg of compound Int2-8.

[0213] Step 7: Synthesis of compound Int2-9

[0214] Compound Int2-8 (20.0 mg, 83.2 μmol) was dissolved in acetonitrile (0.3 mL), and N-bromosuccinimide (17.8 mg, 99.9 μmol) was added. The mixture was allowed to react at room temperature for 1 h. The reaction mixture was concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain 25.0 mg of compound Int2-9.

[0215] Step 8: Synthesis of compound 14-1

[0216] Compound Int2-9 (30.0 mg, 94.0 μmol) was dissolved in dioxane (0.5 mL), and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (68.3 mg, 188.0 μmol) and N,N-diisopropylethylamine (36.4 mg, 281.9 μmol) were added. The mixture was allowed to react at room temperature for 10 h. The reaction mixture was then concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to afford 20.0 mg of compound 14-1.

[0217] LC-MS (ESI): m / z = 554.0 [M+H] +

[0218] Example 1: Synthesis of 2-(2-(3-chloro-4-((dimethylamino)methyl)phenyl)-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 (Compound 1)

[0219] Step 1: Synthesis of compound 1-1

[0220] Dissolve the raw material 4-bromo-1-(bromomethyl)-2-chlorobenzene (500 mg) in acetonitrile (10 mL), add dimethylamine hydrochloride (172 mg), N,N-diisopropylethylamine (341 mg, 459.37 μL), and potassium carbonate (486 mg). React at 40°C for 15 hours. Completion of the reaction was monitored by LCMS. The system was filtered, the solvent was evaporated under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 3:1 to obtain compound 1-1 (237 mg).

[0221] Step 2: Synthesis of compound 1-2

[0222] Dissolve raw material 1-1 (207 mg) in 1,4-dioxane (5 mL), add pinacol diboronate (317 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (122 mg), and potassium acetate (245 mg). Replace the atmosphere with argon three times, using an argon shield. Heat to 100°C and react for 10 hours. Completion of the reaction is monitored by LCMS. Evaporate the solvent under reduced pressure, and column chromatography using dichloromethane:methanol = 50:1 yields compound 1-2 (40 mg).

[0223] Step 3: Synthesis of 2-(2-(3-chloro-4-((dimethylamino)methyl)phenyl)-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

[0224] Intermediate Int-1 (90 mg) was dissolved in 1,4-dioxane (15 mL), and starting material 1-2 (79 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (15 mg), potassium carbonate (55 mg), and water (3 mL) were added. The atmosphere was replaced with argon three times, and the mixture was heated to 75°C and allowed to react for 6 hours. The reaction was monitored by LCMS. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile. B%: 45% to 75% over 7.5 min, peak gradient: 65%, RT: 8.5 min, 25 mL / min). The product was lyophilized to yield 18.6 mg of the title compound.

[0225] LC-MS (ESI): m / z = 787.2 [M+H] +

[0226] 1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.41(s,1H),8.11–8.02(m,3H),7.98( d,J=2.1Hz,1H),7.71(dd,J=9.0,2.1Hz,1H),7.63(d,J=8.0Hz,1H),5.40(s,2 H),4.53(d,J=12.4Hz,1H),3.51(m,5H),3.25(m,1H),3.05–2.93(m,3H),2.8 3(m,1H),2.68–2.64(m,1H),2.40(s,3H),2.22(s,6H),1.21(t,J=7.6Hz,3H).

[0227] Example 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((3-methoxyazetidin-1-yl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 2)

[0228] Step 1: Synthesis of compound 2-2

[0229] 3-Methoxy-azetidine hydrochloride (64 mg) was weighed and dissolved in acetonitrile (5 mL). Potassium carbonate (278 mg) was added and stirred for 0.5 h. Raw material 2-1 (200 mg) was added and reacted at 60°C for 3 h. Completion of the reaction was monitored by TLC. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol = 97 / 3) to afford compound 2-2 (138 mg).

[0230] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((3-methoxyazetidin-1-yl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0231] Compound 2-2 (26 mg) was dissolved in dioxane (5 mL) and water (1 mL), and intermediate Int-1 (60 mg), potassium phosphate (54 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.3 mg) were added at room temperature. After the addition was complete, the reaction solution was heated to 90°C under nitrogen protection for 10 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, concentrated, and separated by preparative chromatography (chromatographic column: YMC C 18; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 50%, B is acetonitrile, 25 mL / min) to obtain 13.2 mg of the target compound.

[0232] LC-MS (ESI): m / z = 795.2 [M+H] +

[0233] 1 H NMR(400MHz, DMSO-d6)δ8.20(s,1H),8.04(dd,J=8.4,3.1Hz,3H),7.95(d,J=2.1 Hz,1H),7.69(dd,J=8.7,2.1Hz,1H),7.39(d,J=7.9Hz,2H),5.37(s,2H),4.51(d, J=12.3Hz,1H),3.97(m,1H),3.61(s,2H),3.50(s,4H),3.13(s,3H),2.99(s,2H), 2.84(dd,J=7.7,5.5Hz,4H),2.62(m,1H),2.33(s,3H),1.19(m,3H),0.83(m,2H).

[0234] Example 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-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 (Compound 3)

[0235] Step 1: Synthesis of compound 3-2

[0236] Disperse p-dibromobenzene (600 mg), compound 3-1 (347 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP, 159 mg), sodium tert-butyl alcohol (1.22 g) and Pd2(dba)3 (233 mg) in toluene (10 mL), protect with nitrogen, stir and react at 100 ° C for 12 hours, concentrate the solvent under reduced pressure, and obtain compound 3-2 (300 mg) by column chromatography (dichloromethane / methanol = 20 / 1).

[0237] Step 2: Synthesis of compound 3-3

[0238] Compound 3-2 (170 mg), pinacol diboronate (220 mg), potassium acetate (196 mg) and Pd(dppf)Cl2 (97 mg) were dispersed in dioxane (3 mL), protected by nitrogen, and stirred at 80°C for 6 hours. The reaction solvent was concentrated and column chromatography (dichloromethane / methanol = 20 / 1) gave compound 3-3 (150 mg).

[0239] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-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

[0240] Intermediate Int-1 (65 mg), compound 3-3 (50 mg), potassium phosphate (46 mg), and Pd(dppf)Cl2 (11 mg) were dispersed in water (1 mL) / dioxane (4 mL) and stirred at 80°C under nitrogen for 6 hours. The solvent was directly concentrated and separated by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-70%, B: acetonitrile, 25 mL / min) to obtain 6.7 mg of the title compound.

[0241] LC-MS (ESI): m / z = 794.2 [M+H] +

[0242] 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.46(s,1H),8.05(d,J=8.6Hz,1H),7.97(d,J=2.1Hz,1H),7. 91(d,J=8.6Hz,2H),7.71(dd,J=8.8,2.1Hz,1H),6.50(d,J=8.6Hz,2H),5.36(s,2H),4.52(d,J=12.3 Hz,1H),3.96(t,J=7.3Hz,2H),3.69–3.59(m,2H),3.54–3.45(m,3H),3.25–3.15(m,2H),3.06–2.92 (m,3H),2.81(d,J=11.0Hz,1H),2.69–2.59(m,1H),2.42(s,3H),2.11(s,6H),1.20(t,J=7.4Hz,3H).

[0243] Example 4: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((2-methylmorpholinyl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 4)

[0244] Step 1: Synthesis of Compound 4-1: Dissolve the starting material p-bromobenzyl bromide (500 mg) in acetonitrile (15 mL), add (2S)-2-methylmorpholine hydrochloride (276 mg), N,N-diisopropylethylamine (311 mg), and potassium carbonate (828 mg). React at 40°C for 15 hours. Completion of the reaction was monitored by LCMS. Filter the system, remove the solvent under reduced pressure, and perform column chromatography using petroleum ether:ethyl acetate in a ratio of 5:1. This affords Compound 4-1 (500 mg).

[0245] Step 2: Synthesis of compound 4-2

[0246] Dissolve the starting compound 4-1 (540 mg) in 1,4-dioxane (15 mL), add pinacol diboronate (761 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (219 mg), and potassium acetate (588 mg, 6.00 mmol). Replace the atmosphere with argon three times, using an argon shield. Heat to 100°C and react for 10 hours. Completion of the reaction was monitored by LCMS. Evaporate the solvent under reduced pressure, and column chromatography was performed using a 5:1 ratio of petroleum ether to ethyl acetate to afford compound 4-2 (580 mg).

[0247] Step 3: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((2-methylmorpholinyl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0248] Intermediate Int-1 (50 mg) was dissolved in 1,4-dioxane (15 mL), and compound 4-2 (27.23 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (7.84 mg), potassium carbonate (29.62 mg), and water (3 mL) were added. The atmosphere was replaced with argon three times, and the mixture was heated to 75°C and allowed to react for 6 hours. Completion of the reaction was monitored by LCMS. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile, B%: 35% to 65% in 9.6 min, peak gradient: 58%, RT: 8.5 min, 25 mL / min). The product was then lyophilized to yield 23 mg of the title compound.

[0249] LC-MS (ESI): m / z = 809.3 [M+H] +

[0250] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.39(s,1H),8.06(m,3H),7.97(d,J=2.0Hz,1H),7.7 0(dd,J=8.9,2.1Hz,1H),7.45(m,2H),5.39(s,2H),4.53(d,J=12.3Hz,1H),3.75–3.70(m,1 H),3.54–3.45(m,7H),3.24(m,1H),3.07–2.92(m,3H),2.82(m,1H),2.71–2.58(m,3H),2.3 9(s,3H),2.04(m,1H),1.73(t,J=10.3Hz,1H),1.21(t,J=7.4Hz,3H),1.01(d,J=6.2Hz,3H).

[0251] Example 5: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((2-methylmorpholinyl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 5)

[0252] Step 1: Synthesis of compound 5-1

[0253] Dissolve p-bromobenzyl bromide (500 mg) in acetonitrile (20 mL), add (R)-2-methylmorpholine (201 mg), potassium carbonate (829 mg), and N,N-diisopropylethylamine (311 mg), and react at 40°C for 15 hours. LCMS monitors the reaction completion. Filter the system, remove the solvent under reduced pressure, and perform column chromatography using petroleum ether:ethyl acetate (5:1) to obtain compound 5-1 (510 mg).

[0254] Step 2: Synthesis of compound 5-2

[0255] Dissolve raw material 5-1 (540 mg) in 1,4-dioxane (10 mL), add pinacol diboronate (762 mg, 3.00 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (219 mg), and potassium acetate (588 mg). Replace the atmosphere with argon three times, using an argon shield. Heat to 100°C and react for 10 hours. Completion of the reaction is monitored by LCMS. Evaporate the solvent under reduced pressure, and column chromatography is performed using a 5:1 ratio of petroleum ether to ethyl acetate to afford compound 5-2 (580 mg).

[0256] Step 3: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-((2-methylmorpholinyl)methyl)phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0257] Intermediate Int-1 (50 mg) was dissolved in 1,4-dioxane (15 mL), and compound 5-2 (25 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (8 mg), potassium carbonate (30 mg, 214.63 μmol), and water (3 mL) were added. The atmosphere was replaced with argon three times, and the mixture was heated to 75°C and allowed to react for 6 hours. Completion of the reaction was monitored by LCMS. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile, B%: 35% to 65% in 9.6 min, peak gradient: 58%, RT: 8.5 min, 25 mL / min). The product was lyophilized to obtain 29 mg of the title compound.

[0258] LC-MS (ESI): m / z = 809.3 [M+H] +

[0259] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.51(s,1H),8.06(m,3H),7.98(d,J=2.1Hz,1H),7.7 1(dd,J=8.8,2.1Hz,1H),7.45(m,2H),5.39(s,2H),4.53(d,J=12.4Hz,1H),3.75–3.68(m,1 H),3.56–3.46(m,7H),3.25(m,1H),3.00(m,3H),2.84(m,1H),2.70–2.60(m,3H),2.43(s,3 H),2.07–2.00(m,1H),1.73(t,J=10.5Hz,1H),1.21(t,J=7.4Hz,3H),1.02(d,J=6.2Hz,3H).

[0260] Example 6: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((1-(2-fluoroethyl)azetidin-3-yl)oxy)phenyl)-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 (Compound 6)

[0261] Step 1: Synthesis of compound 6-2

[0262] Raw material 6-1 (4 g) and triethylamine (3.51 g) were dissolved in dichloromethane (50 mL). Methanesulfonyl chloride (3.17 g) was added at 0°C and stirred for 1.5 h. p-bromophenol (5.99 g) and cesium carbonate (16.9 g) were then added. The mixture was allowed to react at 25°C for 12 h. Completion of the reaction was monitored by TLC. The reaction mixture was filtered, the filtrate was concentrated, and column chromatography (petroleum ether / ethyl acetate = 90 / 10) was performed to obtain compound 6-2 (7.1 g).

[0263] Step 2: Synthesis of compound 6-3

[0264] Compound 6-2 (7.1 g) was weighed and dissolved in dichloromethane (50 mL). Trifluoroacetic acid (11.9 g) was added under ice-cooling and allowed to react at 25°C for 4 hours. The reaction was monitored by TLC. The reaction solution was concentrated, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 6-3 (1.05 g).

[0265] Step 3: Synthesis of compound 6-4

[0266] Compound 6-3 (200 mg) was weighed and dissolved in acetonitrile (5 mL). Potassium carbonate (363 mg) and fluoroethyl p-toluenesulfonate (287 mg) were added, and the mixture was heated to 60°C for 5 hours. Completion of the reaction was monitored by TLC. The reaction solution was concentrated, extracted with dichloromethane and water, and the organic layer was dried over anhydrous sodium sulfate and concentrated by column chromatography (dichloromethane / methanol = 97 / 3) to afford compound 6-4 (120 mg).

[0267] Step 4: Synthesis of compound 6-5

[0268] Compound 6-4 (120 mg) was dissolved in dioxane (10 mL). Diboronic acid pinacol ester (122 mg), potassium acetate (238 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (32 mg) were added at room temperature. After addition, the reaction mixture was heated to 90°C under nitrogen for 4 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 97 / 3) to afford compound 6-5 (127 mg).

[0269] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((1-(2-fluoroethyl)azetidin-3-yl)oxy)phenyl)-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

[0270] Compound 6-5 (25 mg) was dissolved in dioxane (5 mL) and water (1 mL), and intermediate Int-1 (60 mg), potassium phosphate (54 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.3 mg) were added at room temperature. After the addition was complete, the reaction solution was heated to 90°C under nitrogen protection for 10 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, concentrated, and separated by preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 50%, B is acetonitrile, 25 mL / min) to obtain 13.1 mg of the target compound.

[0271] LC-MS (ESI): m / z = 813.2 [M+H] +

[0272] 1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.47(s,1H),8.08-7.94(m,4H),7.70(dd ,J=9.0,2.1Hz,1H),7.00-6.91(m,2H),5.37(s,2H),4.87(t,J=5.6Hz,1H),4.60 -4.45(m,2H),4.42-4.30(m,1H),3.81(m,2H),3.59-3.45(m,4H),3.13-3.07(m,2H),3.05-2.93(m,3H),2.86-2.76(m,2H),2.71(m,1H),2.68 -2.61(m,1H),2.42(s,3H),1.20(t,J=7.4Hz,3H).

[0273] Example 7: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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 (Compound 7)

[0274] Step 1: Synthesis of compound 7-2

[0275] Compound 2-1 (1 g), compound 7-1 (488.25 mg), and N,N-diisopropylethylamine (1.0 g) were added to anhydrous acetonitrile (5 mL). The reaction was carried out at 70°C. After completion of the reaction, monitored by LCMS, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected and dried, and then eluted with a methanol / dichloromethane (1:20) gradient to obtain compound 7-2 (400 mg).

[0276] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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

[0277] Intermediate Int-1 (50 mg), compound 7-2 (25.00 mg), Pd(dppf)Cl2 (10.47 mg), and potassium phosphate (45.56 mg) were added to water (0.2 mL) and dioxane (0.8 mL). The reaction was carried out at 90°C under an argon atmosphere. After the reaction was completed, the reaction solution was filtered and directly sent to preparative chromatography (chromatographic column: YMC C18 18 mg of the target compound was isolated using mobile phase (A: 0.7% NH4HCO3 in H2O; B: 50%, B: acetonitrile, 25 mL / min). LC-MS: m / z (ESI): 783.2 [M+H] + .

[0278] 1 H NMR(400MHz, DMSO-d6)δ8.43(s,1H),8.05(dd,J=8.3,1.7Hz,3H),7.97(d,J=2.1Hz,1H),7 .70(dd,J=8.7,2.2Hz,1H),7.41(d,J=8.1Hz,2H),5.38(s,2H),5.18(m,1H),4.52(m,1H), 3.68(s,2H),3.61–3.43(m,6H),3.24(s,1H),3.21–3.16(m,1H),3.15–3.09(m,1H),3.07– 2.92(m,3H),2.82(m,1H),2.69–2.61(m,1H),2.40(d,J=2.5Hz,3H),1.20(t,J=7.4Hz,3H).

[0279] Example 8: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(1-(dimethylamino)cyclopropyl)-3-fluorophenyl)-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 (Compound 8)

[0280] Step 1: Synthesis of compound 8-2

[0281] Compound 8-1 (900 mg) was dissolved in toluene (20 mL), followed by the addition of triethylamine (421 mg) and diphenylphosphoryl azide (1010 mg). The mixture was stirred at 110°C under nitrogen for 2 hours. Saturated ammonium chloride solution (5 mL) was then added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the isocyanate intermediate. Dilute hydrochloric acid (5 M, 4 mL) was added to the isocyanate, and the mixture was stirred at 90°C for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 8, extracted with dichloromethane, and the organic phase was concentrated. Compound 8-2 (600 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0282] Step 2: Synthesis of compound 8-3

[0283] Compound 8-2 (350 mg) was dissolved in ethanol (10 mL), and then formaldehyde aqueous solution (1.12 g, 1.03 mL, 37% purity) and formic acid (585 mg, 479.21 μL) were added. Under nitrogen protection, the reaction was stirred at 80°C for 4 hours. The solvent was concentrated under reduced pressure to a small amount of solvent, and saturated sodium bicarbonate solution was added to adjust the pH to about 8. The mixture was extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8-3 (350 mg).

[0284] Step 3: Synthesis of compound 8-4

[0285] Compound 8-3 (200 mg), pinacol diboron (295 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (57 mg) and potassium acetate (228 mg) were dispersed in 1,4-dioxane (4 mL), replaced with nitrogen three times, protected by nitrogen, and stirred at 80°C for 6 h. The reaction solvent was directly concentrated and column chromatography (dichloromethane / methanol = 20 / 1) was performed to obtain crude compound 8-4 (200 mg).

[0286] Step 4: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(1-(dimethylamino)cyclopropyl)-3-fluorophenyl)-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

[0287] Compound 8-4 (33 mg), intermediate INT-1 (50 mg), potassium phosphate (46 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (11 mg) were dispersed in water (1 mL) / dioxane (4 mL) and stirred at 80°C under nitrogen for 4 hours. The solvent was directly concentrated and separated by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 40%-70%, B: acetonitrile, 25 mL / min) to obtain 27 mg of the title compound.

[0288] LC-MS (ESI): m / z = 797.3 [M+H] +

[0289] 1H NMR(400MHz,Chloroform-d)δ11.81(s,1H),9.01(s,1H),8.60(s,1H),8.50(d,J=8.7Hz,1H),8.02(dd,J=7.9,1.6 Hz,1H),7.94(dd,J=10.7,1.6Hz,1H),7.62(d,J=2.0Hz,1H),7.53(dd,J=8.9,2.0Hz,1H),7.36(m,1H),5.69(m,1H ),5.19(s,2H),4.81(d,J=12.8Hz,1H),3.84(t,J=11.8Hz,2H),3.51(t,J=12.6Hz,1H),3.22(d,J=8.0Hz,2H),3.1 0(d,J=14.4Hz,1H),2.83(m,2H),2.57(s,3H),2.28(s,6H),1.37(t,J=7.4Hz,3H),1.06(m,2H),0.93–0.78(m,2H).

[0290] Example 9: Synthesis of 2-(2-(4-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-3-fluorophenyl)-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 (Compound 9)

[0291] Step 1: Synthesis of compound 9-3

[0292] Compound 9-1 (300 mg) and compound 9-2 (193.71 mg) were added to anhydrous acetonitrile (5 mL), followed by DIEA (307.73 mg, 414.73 μL). The reaction was carried out at 65°C. After completion of the reaction, as monitored by LCMS, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected, concentrated, and then eluted with a methanol / dichloromethane (1:20) gradient to afford compound 9-3 (200 mg).

[0293] Step 2: Synthesis of 2-(2-(4-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-3-fluorophenyl)-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

[0294] Intermediate Int-1 (50 mg), compound 9-3 (28.61 mg), Pd(dppf)Cl2 (10.47 mg), and potassium phosphate (45.56 mg) were added to water (0.2 mL) and dioxane (0.8 mL). The reaction was carried out at 90°C under an argon atmosphere. After the reaction was completed, the reaction solution was filtered and directly sent to preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 50%, B is acetonitrile, 25mL / min) to separate and obtain 30mg of the target compound.

[0295] LC-MS: m / z(ESI):825.2[M+H] +

[0296] 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.04(d,J=8.6Hz,1H),7.96(d,J=2.1Hz,1H),7.91(dd,J=7.9,1.6Hz,1H),7.77(dd ,J=10.8,1.6Hz,1H),7.69(d,J=8.4Hz,1H),7.61(t,J=7.8Hz,1H),5.37(s,2H),4.51(m,1H),4.36(s,1H),3.93(d,J=7. 5Hz,1H),3.84–3.73(m,2H),3.57–3.44(m,7H),3.01(d,J=8.1Hz,2H),2.96–2.88(m,1H),2.82–2.75(m,2H),2.63(d,J= 10.4Hz,1H),2.46(s,1H),2.37–2.30(m,3H),1.81(dd,J=9.5,2.2Hz,1H),1.60(d,J=9.7Hz,1H),1.19(t,J=7.5Hz,3H).

[0297] Example 10: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(1-(dimethylamino)cyclobutyl)-3-fluorophenyl)-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 (Compound 10)

[0298] Step 1: Synthesis of compound 10-2

[0299] Compound 10-1 (2.0 g) was dissolved in DMF (30 mL), and sodium hydride (785 mg, 60% purity) was added at 0°C under nitrogen. The reaction was stirred at 0°C for 0.25 hours, and 1,3-dibromopropane (2.08 g) was added. The mixture was diluted with water (20 mL), extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to afford compound 10-2 (1.5 g).

[0300] Step 2: Synthesis of compound 10-3

[0301] Compound 10-2 (1.00 g) was dissolved in dimethyl sulfoxide (20 mL), and potassium carbonate (326 mg) and hydrogen peroxide (3.44 g, 35%) were added with stirring. The temperature was raised to 25° C. and stirred for 12 hours. Water (30 mL) was added to dilute the reaction, and the mixture was extracted with ethyl acetate (50 mL*2). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10-3 (1.00 g).

[0302] Step 3: Synthesis of compound 10-4

[0303] Compound 10-3 (250 mg) was dissolved in dioxane (5 mL), and then hydrochloric acid (4M) aqueous solution (5 mL) was added. The reaction was stirred at 100°C for 6 hours. After cooling to room temperature, ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (MeOH / DCM = 0-10%) was performed to obtain compound 10-4 (200 mg).

[0304] Step 4: Synthesis of compound 10-5

[0305] Compound 10-4 (1.3 g) was dissolved in dioxane (20 mL), and triethylamine (963 mg) and diphenylphosphoryl azide were added. The mixture was stirred at 25°C for 12 hours, and ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A 4M aqueous hydrochloric acid solution (10 mL) was added to the residue, and the mixture was stirred at 70°C for 12 hours. The mixture was cooled to 0°C, and a saturated aqueous potassium carbonate solution was slowly added dropwise until the pH reached 8-9. Ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (methanol / dichloromethane = 0-5%) to give compound 10-5 (780 mg).

[0306] Step 5: Synthesis of compound 10-6

[0307] Compound 10-5 (400 mg) was dissolved in ethanol (15 mL), followed by the addition of formaldehyde (1.06 g, 37% purity) and formic acid (603 mg). The mixture was stirred at 80°C under nitrogen for 5 hours. The reaction solvent was removed by concentration under reduced pressure, and the reaction mixture was rediluted with ethyl acetate. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 9. The mixture was extracted with ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 10-6 (390 mg).

[0308] Step 6: Synthesis of compound 10-7

[0309] Compound 10-6 (60 mg), pinacol diboronate (84 mg), potassium acetate (65 mg) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (18 mg) were dispersed in dioxane (4 mL), protected by nitrogen, and stirred at 90°C for 6 hours. The solvent was removed under reduced pressure, and compound 10-7 (60 mg) was obtained by column chromatography (ethyl acetate / petroleum ether = 0-50%).

[0310] Step 7: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(1-(dimethylamino)cyclobutyl)-3-fluorophenyl)-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

[0311] Compound 10-7 (55 mg), intermediate INT-1 (120 mg), potassium phosphate (182 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (42 mg) were dispersed in a mixed solvent of dioxane (8 mL) and water (1 mL). The mixture was stirred at 80°C under nitrogen protection for 8 hours. The mixture was cooled to room temperature, and ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 30% to 70%, B is acetonitrile, 25 mL / min) to obtain 20 mg of the target compound.

[0312] LC-MS(ESI):m / z(ESI):811.2[M+H] + .

[0313] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.39(s,1H),8.05(d,J=8.6Hz,1H),7.98(d,J=2.0Hz,1H),7.9 1(dd,J=8.0,1.6Hz,1H),7.80–7.66(m,2H),7.25(t,J=7.9Hz,1H),5.40(s,2H),4.53(d,J=12.2Hz,1H ),3.56–3.45(m,3H),3.29–3.18(m,1H),3.05–2.90(m,3H),2.83(d,J=11.0Hz,1H),2.66(t,J=6.4Hz, 1H), 2.40 (s, 3H), 2.35 (t, J = 7.7Hz, 4H), 2.16–1.82 (m, 7H), 1.78–1.65 (m, 1H), 1.21 (t, J = 7.4Hz, 3H).

[0314] Example 11: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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 (Compound 11)

[0315] Step 1: Synthesis of compound 11-2

[0316] Compound 9-1 (200 mg, 634.95 μmol) was dissolved in acetonitrile (1.89 mL), and N,N-diisopropylethylamine (328 mg, 442.38 μL) and 3-fluoroazetidine hydrochloride (142 mg) were added. The mixture was heated to 70°C and stirred for 16 hours. LCMS analysis confirmed the main product. The mixture was cooled to room temperature and extracted with 10 mL of ethyl acetate and 10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford compound 11-2 (196 mg).

[0317] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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. Weigh intermediate Int-1 (110 mg), compound 11-2 (97.32 mg), dissolve in water (1 mL) and 1 Potassium phosphate (167.05 mg) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (19.28 mg) were added to a mixed solvent of 4-dioxane (8 mL). The mixture was stirred at 90°C for 3 hours under a nitrogen atmosphere. LCMS analysis showed the product as the main peak. The mixture was cooled to room temperature, extracted with 5 mL of water and 10 mL of ethyl acetate, and the solvent was evaporated from the organic layer under reduced pressure. The residue was separated by column chromatography (MeOH / DCM = 0-10%) and further separated by reverse-phase high-performance liquid chromatography (chromatographic column: YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate solution; B: acetonitrile. B%: 40%-70% in 8 min, peak gradient: 62%, RT: 8.5 min, 25 mL / min) and lyophilized to obtain 36.9 mg of the target compound.

[0318] LC-MS (ESI): m / z = 801.2 [M+H] +

[0319] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.56(s,1H),8.05(d,J=8.6Hz,1H),7.97(s,1H), 7.92(m,1H),7.79(m,1H),7.71(m,1H),7.54(t,J=7.8Hz,1H),5.40(s,2H),5.25–5.11(m ,1H),4.54(d,J=12.5Hz,1H),3.72(s,2H),3.67–3.46(m,6H),3.28–3.22(m,2H),3.21– 3.15(m,1H),3.03(m,3H),2.84(m,1H),2.68(m,1H),2.45(s,3H),1.21(t,J=7.4Hz,3H).

[0320] Example 12: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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 (Compound 12)

[0321] Step 1: Synthesis of compound 12-1

[0322] 3-(R)-Fluoropyrrolidine hydrochloride (200 mg) was weighed and dissolved in acetonitrile (5 mL). Potassium carbonate (929.1 mg) was added and stirred for 0.5 h. Compound 9-1 (706.9 mg) was added and allowed to react at 60°C for 3 h. Completion of the reaction was monitored by TLC. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol = 97 / 3) to afford compound 12-1 (573 mg).

[0323] Step 2: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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

[0324] Compound 12-1 (27.7 mg) was dissolved in dioxane (5 mL) and water (1 mL). Intermediate Int-1 (60 mg), potassium phosphate (54 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.3 mg) were added at room temperature. After the addition was complete, the reaction solution was heated to 90°C under nitrogen protection for 10 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, concentrated, and separated by preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 45%, B is acetonitrile, 25 mL / min) to obtain 6.3 mg of the target compound.

[0325] LC-MS (ESI): m / z = 815.2 [M+H] +

[0326] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.46(s,1H),8.05(m,1H),7.97(m,1H),7.93(dd,J=7.9,1. 6Hz,1H),7.80(dd,J=10.7,1.6Hz,1H),7.71(dd,J=8.7,2.1Hz,1H),7.58(m,1H),5.39(s,2H),5.2 7(m,1H),5.13(m,1H),4.53(d,J=12.4Hz,1H),3.71(s,2H),3.51(m,3H),3.06-2.94(m,3H),2.86- 2.77(m,3H),2.67(m,3H),2.41(s,3H),2.37(m,1H),2.14(m,1H),1.94-1.78(m,1H),1.21(m,3H).

[0327] Example 13: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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 (Compound 13)

[0328] Step 1: Synthesis of compound 13-1

[0329] 3-(S)-Fluoropyrrolidine hydrochloride (200 mg) was weighed and dissolved in acetonitrile (5 mL). Potassium carbonate (929.1 mg) was added and stirred for 0.5 h. Compound 9-1 (706.9 mg) was added and allowed to react at 60°C for 3 h. Completion of the reaction was monitored by TLC. The reaction mixture was filtered, the filtrate was concentrated, and column chromatography (dichloromethane / methanol = 97 / 3) was performed to obtain compound 13-1 (513 mg).

[0330] Step 2: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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

[0331] Compound 13-1 (27.7 mg) was dissolved in dioxane (5 mL) and water (1 mL). Intermediate Int-1 (60 mg), potassium phosphate (54 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.3 mg) were added at room temperature. After the addition was complete, the reaction solution was heated to 90°C under nitrogen protection for 10 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, concentrated, and separated by preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 45%, B is acetonitrile, 25mL / min) to obtain 7.9mg of the target compound.

[0332] LC-MS (ESI): m / z = 815.2 [M+H] +

[0333] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.53(s,1H),8.04(m,1H),7.97(m,1H),7.93(dd,J=7.9,1.6Hz ,1H),7.79(dd,J=10.7,1.6Hz,1H),7.71(dd,J=8.8,2.1Hz,1H),7.58(m,1H),5.39(s,2H),5.27(m,1 H),5.13(m,1H),4.53(m,1H),3.71(s,2H),3.53-3.48(m,3H),3.01(dd,J=11.4,5.0Hz,3H),2.82(m, 3H),2.73-2.59(m,3H),2.43(s,3H),2.14(m,1H),1.94-1.80(m,1H),1.60-1.45(m,1H),1.20(m,3H).

[0334] Example 14: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-azabicyclo[4.1.0]heptane-6-yl)-7-oxo-2-phenyl-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 14)

[0335] Step 1: Synthesis of compound 14-3

[0336] Compound 14-2 (109.3 mg) and compound 14-1 (100.0 mg) were dissolved in water (0.2 mL) and toluene (2.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (29.2 mg) and cesium carbonate (176.2 mg) were added. The mixture was then microwaved under nitrogen at 100°C for 1.5 h. The reaction was complete. The reaction solution was directly concentrated and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 14-3 (60.0 mg).

[0337] Step 2: Synthesis of compound 14-4

[0338] Compound 14-3 (120.0 mg) was dissolved in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) and allowed to react at room temperature for 30 min. The reaction mixture was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated to obtain a crude product of compound 14-4 (120 mg).

[0339] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-azabicyclo[4.1.0]heptane-6-yl)-7-oxo-2-phenyl-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0340] Compound 14-4 (90.0 mg) and compound 14-5 (5.8 mg) were dissolved in N,N-dimethylformamide (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90.6 mg) and 1-hydroxybenzotriazole (2.1 mg) were added and allowed to react at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated and purified by preparative chromatography (column: YMC TA column; mobile phase: A: 7 mmol NH4HCO3 aqueous solution; B: acetonitrile, B%: 40% to 70%, 40 mL / min) to obtain 15.0 mg of the title compound.

[0341] LC-MS (ESI): m / z = 707.2 [M+H] + ;

[0342] 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.30(s,1H),8.17-8.08(m,2H),8.05(d,J=8.8Hz,1H),7.95(s,1H),7.73-7.66(m,1H),7.66 -7.59(m,2H),7.56 -7.49(m,1H),5.41-5.28(m,2H),4.05-3.95(m,1H),3.92-3.82(m,1H),3.73-3.62(m,1H),3.23-3.17(m,1H),3.15-3.06(m,1H),3.04- 2.93(m,1H),2.76(s,1H),2.36(s,3H),2.16-2.07(m,1H),2.02-1.92(m,1H),1.92-1.82(m,1H),1.80-1.69(m,1H),1.29-1.21(m,3H).

[0343] Example 15: Synthesis of N-(4-bromo-1H-indazol-7-yl)-2-(2-(3,6-dihydro-2H-pyran-4-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 (Compound 15)

[0344] Step 1: Synthesis of compound 15-1

[0345] Dissolve the raw material 4-bromo-7-nitro-1H-indazole (500 mg) in tetrahydrofuran (50 mL), place in an ice bath under argon protection, add sodium hydride (124 mg, 60% purity), and stir for 15 minutes. Add 2-(chloromethoxy)ethyltrimethylsilane (414 mg). Warm the mixture to room temperature and react for 5 hours. TLC monitors the reaction completion. Quench the mixture with ice water, add 20 mL of water, extract with 40 mL of ethyl acetate, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Column chromatography is performed using a 5:1 ratio of petroleum ether to ethyl acetate. Compound 15-1 (445 mg) is obtained.

[0346] Step 2: Synthesis of compound 15-2

[0347] Dissolve raw material 15-1 (445 mg) in ethanol (20 mL), add iron powder (534 mg) and a saturated aqueous solution of ammonium chloride (646 mg). Heat to 80°C and react for 10 hours. Completion of the reaction is monitored by LCMS. Filter the mixture while hot, and evaporate the solvent from the filtrate under reduced pressure. Add 20 mL of water to the mixture, extract with 40 mL of ethyl acetate, separate the layers, and wash the organic phase once with a saturated aqueous sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Column chromatography using dichloromethane:methanol = 50:1 yields compound 15-2 (140 mg).

[0348] Step 3: Synthesis of compound 15-3

[0349] Dissolve the raw material Int-2 (500 mg) in N,N-dimethylformamide (10 mL), add ethyl 2-bromoacetate (235 mg) and N,N-diisopropylethylamine (378 mg, 509.54 μL). Reaction is allowed to proceed at 25°C for 15 hours. LCMS monitors the reaction completion. Pour the reaction system into 40 mL of ice water. Solids precipitate, filter, and spin-dry the filter cake to obtain compound 15-3 (368 mg).

[0350] Step 4: Synthesis of compound 15-4

[0351] Dissolve raw material 15-3 (368 mg) in 1,4-dioxane (100 mL), add 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (181 mg), 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (105 mg), potassium carbonate (297 mg), and water (20 mL). Replace the atmosphere with argon three times, using argon as a protective atmosphere. Heat to 75°C and react for 6 hours. Completion of the reaction was monitored by LCMS. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography using dichloromethane:methanol = 30:1. This afforded compound 15-4 (290 mg).

[0352] Step 5: Synthesis of compound 15-5

[0353] The raw material 15-4 (270 mg) was dissolved in tetrahydrofuran (10 mL) and an aqueous solution of lithium hydroxide (38 mg) was added. The mixture was stirred at room temperature for 5 hours and the reaction was monitored by LCMS. 15 mL of water was added to the system and extracted with 10 mL of ethyl acetate. The aqueous phase was adjusted to pH 2-3 with 3N dilute hydrochloric acid. Solid precipitated and was extracted with 30 mL of dichloromethane. The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain compound 15-5 (216 mg).

[0354] Step 6: Synthesis of compound 15-6

[0355] The raw material 15-5 (155 mg) was dissolved in N,N-dimethylformamide (5 mL), and 15-2 (130 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (179 mg), and N,N-diisopropylethylamine (103 mg, 137.81 μL) were added. The reaction was allowed to react at room temperature for 3 hours, and the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was separated and washed once with saturated sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography was performed using petroleum ether:ethyl acetate = 3:1 to obtain compound 15-6 (205 mg).

[0356] Step 7: Synthesis of compound 15-7

[0357] The raw material 15-6 (185 mg) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (78 mg) was added. The reaction was allowed to react at room temperature for 5 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to 14 with a 4N aqueous sodium hydroxide solution. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The organic phase was separated and washed once with a saturated sodium chloride aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 15-7 (109 mg).

[0358] Step 8: Synthesis of compound 15-8

[0359] Dissolve the raw material 15-7 (99 mg) in N,N-dimethylformamide (5 mL), add 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (24 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg), and 1-hydroxybenzotriazole (4 mg). React at room temperature for 2 hours, and monitor the reaction completion by LCMS. Add 20 mL of water to the system, extract with 40 mL of ethyl acetate, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. This gives the crude product 15-8 (110 mg), which is directly used in the next step.

[0360] Step 9: Synthesis of N-(4-bromo-1H-indazol-7-yl)-2-(2-(3,6-dihydro-2H-pyran-4-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

[0361] Dissolve raw material 15-8 (100 mg) in dichloromethane (5 mL) and add trifluoroacetic acid (54 mg). Allow to react at room temperature for 15 hours. Monitor the reaction by LCMS. Spin dry, then analyze by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile. B%: 35% to 65% in 8 min, gradient: 50%, RT: 7.2 min, 25 mL / min), and lyophilize to obtain 19.5 mg of the title compound.

[0362] LC-MS (ESI): m / z = 718.1 [M+H] +

[0363] 1 H NMR (400MHz, DMSO-d6) δ13.31(s,1H),10.77(s,1H),8.53(s,1H),8.09(s,1H),7.50(s,1H),7.29(d,J=7.9Hz,1H),6.83(s,1H),5.25(s,2H),4.51 (d,J=12.5Hz,1H),4.24(m,2H),3.80(t,J=5.5Hz,2H),3.49(m,3H),3.24 (m,1H),2.98(m,3H),2.81(m,1H),2.64(m,1H),2.44(s,3H),1.21(m,4H).

[0364] Example 16: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1-hydroxy-8-azaspiro[4.5]dec-8-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 16)

[0365] Step 1: Synthesis of compound 16-2

[0366] Compound 16-1 (800 mg) was dissolved in a dioxane hydrochloride solution (4 M, 16 mL), stirred and reacted at 25° C. for 2 hours, and concentrated under reduced pressure to obtain compound 16-2 (590 mg).

[0367] Step 2: Synthesis of compound 16-3

[0368] The intermediates Int1-1 (400 mg) and 16-2 (572 mg) were dissolved in dimethyl sulfoxide (20 mL), and N,N-diisopropylethylamine (780 mg) was added with stirring. The temperature was raised to 90°C and stirred for 48 hours. Water (30 mL) was added to dilute the reaction, and the mixture was extracted with ethyl acetate (50 mL*2). The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM = 0-5% to give compound 16-3 (300 mg).

[0369] Step 3: Synthesis of compound 16-4

[0370] Compound 16-3 (400 mg) was dissolved in tetrahydrofuran (10 mL), and then sodium borohydride (42 mg) was added. The mixture was stirred under nitrogen protection at 70°C for 6 hours. After cooling to room temperature, ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (MeOH / DCM = 0-10%) was performed to obtain compound 16-4 (240 mg).

[0371] Step 4: Synthesis of compound 16-5

[0372] Compound 16-4 (300 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (464.01 mg, 2 mL) was added. The reaction was stirred at 25 ° C for 2 hours, concentrated under reduced pressure, and the residue was added with dichloromethane (20 mL) for redissolution. The mixture was cooled to 0 ° C, and saturated sodium carbonate aqueous solution was slowly added dropwise until the pH reached 10-11. Extraction was performed, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 16-5 (200 mg).

[0373] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1-hydroxy-8-azaspiro[4.5]dec-8-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0374] Compound 16-5 (35 mg) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (95 mg) were dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg) and 1-hydroxybenzotriazole (24 mg) were added, and the mixture was stirred at 25°C for 12 hours. The reaction solution was purified by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH₄HCO₃ in H₂O; B%: 40%-70%, B: acetonitrile, 25 mL / min) to afford 20 mg of the title compound.

[0375] LC-MS(ESI):m / z(ESI):771.3[MH] - .

[0376] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.47(s,1H),8.03(d,J=8.5Hz,1H),7.96(d,J=2.0Hz,1H),7.72(dd,J= 8.8,2.1Hz,1H),5.20(s,2H),4.61–4.32(m,2H),3.78–3.69(m,2H),3.58(t,J=5.5Hz,1H),3.54–3.43(m,3H) ,3.25–3.18(m,1H),3.16–3.08(m,2H),3.00–2.86(m,3H),2.76(d,J=11.0Hz,1H),2.58(d,J=11.1Hz,1H),2. 41(s,3H),1.90–1.77(m,1H),1.68–1.58(m,3H),1.55–1.43(m,3H),1.41–1.25(m,2H),1.15(t,J=7.4Hz,3H).

[0377] Example 17: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((isopropyl(methyl)amino)methyl)phenyl)-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 (Compound 17)

[0378] Step 1: Synthesis of compound 17-2

[0379] Compound 9-1 (500 mg) and compound 17-1 (174.14 mg) were added to anhydrous acetonitrile (3 mL), followed by DIEA (410.30 mg, 552.97 μL). The reaction was carried out at 65°C. After completion of the reaction, monitored by LCMS, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected and dried, and then eluted with a methanol / dichloromethane (1:20) gradient to obtain compound 17-2 (320 mg).

[0380] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((isopropyl(methyl)amino)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0381] Compound Int-1 (30 mg), compound 17-2 (15.82 mg), Pd(dppf)Cl2 (6.28 mg), and cesium carbonate (41.96 mg) were added to water (0.2 mL) and dioxane (0.8 mL). The reaction was carried out at 90°C under an argon atmosphere. After completion of the reaction, the reaction solution was filtered and directly transferred to a preparative chromatography column (YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 40%-70%, B: acetonitrile, 25 mL / min) to obtain 5 mg of the title compound. LC-MS: m / z (ESI): 799.6 [M+H] + .

[0382] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.57(d,J=1.9Hz,1H),8.05(d,J=8.6Hz,1H),7.97(d,J=2 .1Hz,1H),7.91(dd,J=7.9,1.6Hz,1H),7.74(m,2H),7.58(m,1H),5.39(s,2H),4.54(d,J=12.4Hz ,1H),3.56(s,2H),3.52(d,J=12.1Hz,3H),3.02(d,J=10.3Hz,2H),2.90–2.80(m,2H),2.66(d,J= 7.4Hz,1H),2.44(s,3H),2.09(s,3H),2.07(s,3H),1.23–1.19(m,3H),1.03(s,3H),1.02(s,3H).

[0383] Example 18: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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 (Compound 18)

[0384] Step 1: Synthesis of compound 18-1

[0385] 3-(R)-Fluoropyrrolidine hydrochloride (169 mg, 1.35 mmol, HC) and cesium carbonate (1.32 g, 4.04 mmol) were dispersed in acetonitrile (6 mL). After stirring at room temperature for 20 minutes, compound 2-1 (400 mg, 1.35 mmol) was added. The temperature was raised to 60°C and stirred for 4 hours. The reaction was monitored by TLC. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 18-1 (330 mg).

[0386] Step 2: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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

[0387] Compound 18-1 (37 mg), intermediate Int-1 (70 mg), potassium phosphate (64 mg), and Pd(dppf)Cl2 (15 mg) were dispersed in water (1 mL) / dioxane (4 mL) and stirred at 90°C under nitrogen for 6 hours. The solvent was concentrated and purified by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-70%, B: acetonitrile, 25 mL / min) to yield 30 mg of the title compound.

[0388] LC-MS (ESI): m / z = 797.2 [M+H] +

[0389] 1H NMR(400MHz,Chloroform-d)δ11.80(s,1H),9.16(s,1H),8.59(s,1H),8.47(d,J=8.7H z,1H),8.21(d,J=8.0Hz,2H),7.63–7.41(m,4H),5.67(d,J=12.9Hz,1H),5.34–5.07(m, 3H),4.80(d,J=12.9Hz,1H),3.84(d,J=14.1Hz,4H),3.52(d,J=14.0Hz,1H),3.20(d,J =7.8Hz,2H),3.12–2.67(m,7H),2.57(s,3H),2.21–2.13(m,1H),1.35(t,J=7.4Hz,3H).

[0390] Example 19: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-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 (Compound 19)

[0391] Synthesis steps refer to Example 18

[0392] LC-MS (ESI): m / z = 797.2 [M+H] +

[0393] 1 H NMR(400MHz,Chloroform-d)δ11.84(s,1H),9.18(s,1H),8.62(s,1H),8.50(d,J=8.7Hz ,1H),8.24(d,J=8.0Hz,2H),7.61(d,J=2.0Hz,1H),7.58–7.46(m,3H),5.71(d,J=13.1Hz ,1H),5.35–5.13(m,3H),4.83(d,J=12.7Hz,1H),3.85(d,J=10.1Hz,4H),3.53(s,1H),3. 24(d,J=7.8Hz,2H),3.16–2.68(m,7H),2.60(s,3H),2.20(m,1H),1.39(t,J=7.5Hz,3H).

[0394] Example 20: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((4-fluoropiperidin-1-yl)methyl)phenyl)-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 (Compound 20)

[0395] Step 1: Synthesis of compound 20-1

[0396] Compound 2-1 (200 mg) and 4-fluoropiperidine hydrochloride (103.41 mg) were added to anhydrous acetonitrile (4 mL), followed by DIEA (348.13 mg, 469.17 μL). The reaction was allowed to proceed at 70°C for 2 hours. After completion of the reaction, monitored by LCMS, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected and eluted with a methanol / dichloromethane (1:20) gradient to afford compound 20-1 (120 mg).

[0397] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((4-fluoropiperidin-1-yl)methyl)phenyl)-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

[0398] Intermediate Int-1 (110 mg), compound 20-1 (100.49 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19.28 mg), and potassium phosphate (167.05 mg) were added to water (1 mL) and dioxane (8 mL). The reaction was carried out at 90°C under an argon atmosphere for 3 hours. After completion of the reaction, the reaction solution was filtered, concentrated, and eluted with a gradient of methanol / dichloromethane (1:20). The product was then separated by preparative reverse-phase HPLC (column: YMC TA; mobile phase: A: 7 mmol aqueous ammonium bicarbonate solution; B: acetonitrile, B%: 45%-75%, 18 mL / min) to obtain 10 mg of the title compound. LC-MS: m / z (ESI): 811.2 [M+H] + .

[0399] 1 H NMR (400MHz, DMSO-d6) δ8.06(m,4H),7.94(s,1H),7.68(d,J=8.4Hz,1H),7.44(d,J=8.0Hz,2H) ,5.37(s,2H),4.75(s,1H),4.63(s,1H),4.52(d,J=12.2Hz,1H),3.52(s,2H),3.49–3.42(m,3H) ,3.26–3.18(m,1H),3.02(d,J=7.7Hz,2H),2.91(t,J=12.0Hz,1H),2.80(d,J=10.8Hz,1H),2.6 9–2.62(m,2H),2.36–2.25(m,5H),1.92–1.78(m,2H),1.77–1.65(m,2H),1.21(t,J=7.4Hz,3H).

[0400] Example 21: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(6-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-5-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 21)

[0401] Step 1: Synthesis of compound 21-1

[0402] Dimethylamine hydrochloride (54.3 mg) was weighed and dissolved in acetonitrile (5 mL). Potassium carbonate (138.2 mg) was added and stirred at room temperature for 30 min. Compound 9-1 (209.6 mg) was added and the reaction mixture was heated to 60°C for 3 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated, and column chromatography (dichloromethane / methanol = 97 / 3) was performed to obtain compound 21-1 (76.5 mg).

[0403] Step 2: Synthesis of compound 21-2

[0404] Compound 21-1 (76.5 mg) was dissolved in dioxane (5 mL) and water (1 mL). Intermediate Int1-1 (182 mg), potassium phosphate (174.4 mg), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (20.0 mg) were added at room temperature. After addition, the reaction mixture was heated to 90°C under nitrogen for 10 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 96 / 4) to afford compound 21-2 (153 mg).

[0405] Step 3: Synthesis of compound 21-3

[0406] Compound 21-2 (153 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (236.6 mg) was added at room temperature. After the addition, the reaction mixture was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was concentrated to obtain compound 21-3 (128 mg).

[0407] Step 4: Synthesis of compound 21-4

[0408] Compound 21-3 (60 mg) was dissolved in N,N-dimethylformamide (5 mL). 6-Methoxy-7-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (23.5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.6 mg), and 1-hydroxybenzotriazole (2.6 mg) were added at room temperature. After addition, the reaction mixture was incubated at 25°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 96 / 4) to afford compound 21-4 (58 mg).

[0409] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(6-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-5-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0410] Compound 21-4 (58 mg) was dissolved in N,N-dimethylformamide (5 mL), and sodium ethanethiolate (121 mg) was added. After the addition was complete, the reaction solution was reacted at 100°C for 6 hours. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 80%, B is acetonitrile, 25 mL / min) to obtain 5.5 mg of the title compound.

[0411] LC-MS (ESI): m / z = 810.2 [M+H] +

[0412] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),9.63(s,1H),8.14(m,1H),8.05(d,J=8.6Hz,1H),7.97(d,J=2 .1Hz,1H),7.92(dd,J=7.9,1.6Hz,1H),7.79(dd,J=10.8,1.6Hz,1H),7.71(dd,J=8.9,2.1Hz,1H),7. 56(m,1H),6.71(d,J=2.4Hz,1H),5.40(s,2H),4.56(d,J=12.4Hz,1H),3.60-3.43(m,6H),3.06(s,1 H),3.04(s,2H),2.90-2.82(m,1H),2.70(s,3H),2.68-2.61(m,1H),2.18(s,6H),1.23-1.18(m,3H).

[0413] Example 22: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 22)

[0414] Synthesis of Intermediate 22-14

[0415] 22-14-SM (0.1 g, 478.3 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (81.1 mg, 526.1 μmol) were dissolved in dichloromethane (2.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (275.1 mg, 1.4 mmol) and 1-hydroxybenzotriazole (6.5 mg, 47.8 μmol) were added and reacted at room temperature for 1 h. The reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to afford 22-14 (50.0 mg). LC-MS (ESI): m / z = 346.2 [M+H] +

[0416] Step 1: Synthesis of compound 22-3

[0417] Compound 22-2 (5.1 g) was dissolved in a 6 M aqueous hydrochloric acid solution (19.2 mL). A solution of sodium nitrite (2.2 g, 31.9 mmol) dissolved in water (24.0 mL) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Urea (191.6 mg, 3.2 mmol) was then added to consume the excess sodium nitrite. The above solution was then added to a solution of intermediate Int2-1 (6.0 g) dissolved in water (180.0 mL). The mixture was allowed to react at room temperature for 1.5 h. A solution of sodium acetate (9.4 g) in water (180 mL) was then added dropwise, and the mixture was stirred at room temperature for 12 h. The reaction was complete. The reaction mixture was filtered, and the filter cake was washed with water and dried to yield 22-3 (12.0 g, crude product).

[0418] Step 2: Synthesis of compound 22-4

[0419] Compound 22-3 (3.3 g) was dissolved in methanol (15.0 mL), and sodium methoxide solution (5.4 M, 14.2 mL) was added. The mixture was then reacted at 100°C for 8 h. The reaction was complete. The reaction solution was diluted with water (100.0 mL) and extracted with ethyl acetate (100.0 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-4 (3.1 g, crude product).

[0420] Step 3: Synthesis of compound 22-5

[0421] Compound 22-4 (11.0 g) was dissolved in water (50.0 mL) and ethanol (50.0 mL), and copper sulfate (23.8 g) and aqueous ammonia (25.0 mL) were added. The mixture was then reacted at 90°C for 2 h. The reaction was complete. The reaction solution was diluted with a mixture of dichloromethane and methanol (10:1) and filtered through celite. The filtrate was concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) and filter cake column chromatography (dichloromethane / methanol gradient elution under reduced pressure) to give compound 22-5 (7.8 g).

[0422] Step 4: Synthesis of compound 22-6

[0423] Compound 22-5 (3.0 g) was dissolved in N,N-dimethylformamide (10.0 mL). t-Butyl nitrite (2.6 g) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Water (5.0 mL) was then added, and the mixture was allowed to react at 80°C for another 30 min. Upon completion of the reaction, the reaction mixture was diluted with water (40.0 mL) and extracted with ethyl acetate (40.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 22-6 (3.4 g crude product).

[0424] Step 5: Synthesis of compound 22-7

[0425] Compound 22-6 (3.4 g) was dissolved in phosphorus oxychloride (10.0 mL) and reacted at 90°C for 1 h. Upon completion of the reaction, the reaction solution was concentrated to dryness, and saturated sodium bicarbonate solution (20.0 mL) was added. The mixture was then extracted with ethyl acetate (40.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Column chromatography (petroleum ether / ethyl acetate gradient elution under reduced pressure) afforded compound 22-7 (1.2 g).

[0426] Step 6: Synthesis of compound 22-8

[0427] Compound 22-7 (740.0 mg) was dissolved in tetrahydrofuran (10.0 mL), followed by the addition of ferric triacetylacetonate (41.7 mg). Ethylmagnesium bromide (2M, 1.6 mL) was added dropwise under nitrogen at -20°C, and the mixture was allowed to react at -20°C for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain compound 22-8 (350.0 mg).

[0428] Step 7: Synthesis of compound 22-10

[0429] Compound 22-8 (150.0 mg) was dissolved in dioxane (2.0 mL) and water (0.4 mL). Intermediate 22-9 (303.8 mg), palladium acetate (22.2 mg, 97.8 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (46.6 mg, 97.8 μmol), and cesium carbonate (478.0 mg, 1.5 mmol) were added. The mixture was then reacted at 100°C for 1 h under nitrogen. The reaction was complete. The reaction solution was directly concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 22-10 (120.0 mg).

[0430] Step 8: Synthesis of compound 22-11

[0431] Compound 22-10 (120.0 mg) was dissolved in hydrogen bromide and acetic acid solution (2.0 ml, 33% wt) and reacted at 90°C for 24 h. Upon completion of the reaction, the reaction solution was slowly added to a saturated sodium bicarbonate solution (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was directly concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 22-11 (80.0 mg).

[0432] Step 9: Synthesis of compound 22-12

[0433] Compound 22-11 (80.0 mg) was dissolved in acetonitrile (1.0 mL), and N-bromosuccinimide (43.8 mg) was added. The mixture was allowed to react at room temperature for 1 h. Upon completion of the reaction, the reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to afford compound 22-12 (90.0 mg).

[0434] Step 10: Synthesis of compound 22-13

[0435] Compound 22-12 (60.0 mg) was dissolved in 1.0 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (53.3 mg) was added, followed by N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (65.0 mg). The mixture was allowed to react at room temperature for 10 hours. The reaction mixture was then directly mixed and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 22-13 (45.0 mg).

[0436] Step 11: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0437] Compound 22-13 (20.0 mg) was dissolved in water (60.0 μL) and dioxane (0.3 mL). 1,1-Bis(diphenylphosphino)ferrocenepalladium dichloride (6.5 mg, 8.9 μmol), potassium phosphate (25.2 mg, 119.1 μmol), and compound 22-14 (41.1 mg) were added. The mixture was reacted at 90°C for 2 h under nitrogen. The reaction was complete. The reaction solution was directly purified by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B: 40%-70%, B: acetonitrile, 25 mL / min) to obtain 10.0 mg of the title compound.

[0438] LC-MS (ESI): m / z = 810.2 [M+H] + ;

[0439] 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.53(s,1H),8.09-8.04(m,1H),8.02-7.96(m,2H),7.96-7.91(m,1H),7.74-7.63 (m,2H),5.69(s,1H),5.56-5.44(m,1H),5.44-5.26(m,2H),4.39(d,J=18.4Hz,1H),4.21-4.04(m,2H),3.99(s,1H),3.61 -3.55(m,6H),3.50-3.48(m,1H),2.88-2.81(m,1H),2.70-2.65(m,1H),2.44(s,3H),2.43-2.37(m,4H),1.28-1.20(m,3H).

[0440] Example 23: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 23)

[0441] Step 1: Synthesis of compound 23-2

[0442] Intermediate 22-13 (18.0 mg) was dissolved in N-methylpyrrolidone (0.5 mL), and piperazine (46.2 mg) was added. The mixture was then reacted at 140°C under microwave conditions for 45 min. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 23-2 (30.0 mg).

[0443] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0444] Compound 23-2 (25.0 mg, 36.9 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (11.4 mg) were dissolved in N,N-dimethylformamide (0.3 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.2 mg) and 1-hydroxybenzotriazole (0.9 mg) were added and allowed to react at room temperature for 2 h. The reaction was then allowed to complete. The reaction solution was directly purified by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 40%-70%, B: acetonitrile, 25 mL / min) to obtain 4.5 mg of the title compound.

[0445] LC-MS (ESI): m / z = 813.2 [M+H] + ;

[0446] 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.07(d,J=8.6Hz,1H),8.00-7.98(m,1H),7.97-7.96(m,1 H),7.95-7.91(m,1H),7.72-7.64(m,2H),5.38(s,2H),4.51(d,J=12.5Hz,1H),3.76-3.64(m,3 H),3.62-3.53(m,6H),3.50-3.46(m,1H),3.22(s,1H),3.05-3.01(m,1H),2.96-2.92(m,1H),2 .79-2.75(m,1H),2.68-2.66(m,1H),2.61-2.58(m,1H),2.43-2.37(m,6H),1.24-1.20(m,3H).

[0447] Example 24: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2-fluorophenyl)-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 (Compound 24)

[0448] Step 1: Synthesis of compound 24-1

[0449] Dimethylamine hydrochloride (40 mg) was weighed and dissolved in acetonitrile (5 mL). The mixture was stirred at room temperature for 30 min, and compound 9-1 (154.1 mg) was added. The reaction mixture was heated to 60°C and allowed to react for 3 hours. LCMS monitored the reaction completion. The reaction mixture was filtered, the filtrate was concentrated, and column chromatography (dichloromethane / methanol = 97 / 3) was performed to obtain compound 24-1 (54.6 mg).

[0450] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2-fluorophenyl)-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

[0451] Compound 24-1 (35.4 mg) was dissolved in dioxane (5 mL) and water (1 mL), and intermediate Int-1 (80 mg), potassium phosphate (72 mg), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (8.3 mg) were added at room temperature. After the addition was complete, the reaction solution was heated to 90°C under nitrogen protection for 10 hours. The reaction was completed by LCMS monitoring. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 48%, B is acetonitrile, 25 mL / min) to obtain 14.5 mg of the title compound.

[0452] LC-MS (ESI): m / z = 771.2 [M+H] + .

[0453] 1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.50(s,1H),8.05(d,J=8.6Hz,1H),8.02-7 .95(m,2H),7.71(dd,J=8.7,2.1Hz,1H),7.28(d,J=9.9Hz,2H),5.38(s,2H),4.53 (d,J=12.4Hz,1H),3.57-3.46(m,4H),3.46(s,2H),3.05-2.96(m,3H),2.84(d,J= 11.2Hz,1H),2.71-2.62(m,1H),2.42(s,3H),2.17(s,6H),1.21(t,J=7.4Hz,3H).

[0454] Example 25: Synthesis of 2-(2-(4-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-3,5-difluorophenyl)-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 (Compound 25)

[0455] Step 1: Synthesis of compound 25-2

[0456] The raw material 9-2 (200 mg) and cesium carbonate (1.44 g) were dispersed in acetonitrile (8 mL), stirred at room temperature for 30 minutes, and then compound 25-1 (422 mg) was added. The temperature was raised to 60°C and stirred for 4 hours. The solvent was concentrated under reduced pressure and column chromatography (petroleum ether / ethyl acetate = 4 / 1) was used to obtain compound 25-2 (300 mg).

[0457] Step 2: Synthesis of compound 25-3

[0458] Compound 25-2 (200 mg), pinacol diboronate (250 mg), Pd(dppf)Cl2 (96 mg) and potassium acetate (193 mg) were dispersed in dioxane (4 mL) and stirred at 80°C under nitrogen protection for 4 hours. LCMS monitored the complete conversion of the substrate, and the reaction solution was directly used for the next reaction.

[0459] Step 3: Synthesis of 2-(2-(4-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-3,5-difluorophenyl)-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

[0460] Compound 25-3 (39 mg), intermediate Int-1 (50 mg), potassium phosphate (46 mg), and Pd(dppf)Cl2 (11 mg) were dispersed in water (1.5 mL) / dioxane (4 mL) and stirred at 80°C under nitrogen for 4 hours. The solvent was directly concentrated under reduced pressure to prepare the title compound (chromatographic column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-70%, B: acetonitrile, 25 mL / min) to obtain 13 mg of the title compound.

[0461] LC-MS (ESI): m / z = 843.3 [M+H] +

[0462] 1 H NMR(400MHz,Chloroform-d)δ11.80(s,1H),8.87(s,1H),8.60(s,1H),8.49(d,J=8.7Hz,1H),7.80(d,J=7.6H z,2H),7.63(d,J=2.0Hz,1H),7.59–7.49(m,1H),5.69(d,J=13.2Hz,1H),5.18(s,2H),4.81(d,J=12.9Hz,1H) ,4.42(d,J=2.2Hz,1H),4.17(d,J=8.0Hz,1H),3.88–3.79(m,3H),3.71–3.65(m,1H),3.49(s,2H),3.21(d,J= 8.1Hz,2H),3.12–2.70(m,5H),2.57(s,3H),1.91–1.81(m,1H),1.74(d,J=9.7Hz,1H),1.36(t,J=7.5Hz,3H).

[0463] Example 26: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(8-azaspiro[4.5]dec-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 26)

[0464] The synthesis was carried out according to Example 16, with the main difference being that the raw material 16-1 was replaced with tert-butyl 8-azaspiro[4.5]decane-8-carboxylate.

[0465] LC-MS (ESI): m / z = 757.3 [M+H] +

[0466] Example 27: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-fluoro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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 (Compound 27)

[0467] Step 1: Synthesis of compound 27-1

[0468] Compound 9-1 (100 mg) was dissolved in acetonitrile (5 mL), and 3-fluoroazetidine hydrochloride (39 mg) and potassium carbonate (88 mg) were added. The reaction was allowed to react at 80°C for 15 hours. Completion of the reaction was monitored by LCMS. The system was concentrated and column chromatography was performed using dichloromethane:methanol = 50:1 to obtain compound 27-1 (90 mg).

[0469] Step 2: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-fluoro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-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

[0470] Dissolve the raw material Int-1 (60 mg) in 1,4-dioxane (5 mL), then add the intermediate compound 27-1 (32 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13 mg), potassium carbonate (36 mg), and water (1 mL). Replace the atmosphere with argon three times, then protect with argon. Heat to 75°C and react for 6 hours. Monitor the reaction by LCMS. Concentrate the solution and analyze by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile. B%: 35% to 65% over 8 min, gradient: 60%, RT: 9.3 min, 25 mL / min), and lyophilize to obtain 13 mg of the title compound.

[0471] LC-MS (ESI): m / z = 801.2 [M+H] +

[0472] 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.47(s,1H),8.05(d,J=8.6Hz,1H),8.0 3–7.94(m,2H),7.71(m,1H),7.32–7.21(m,2H),5.38(s,2H),5.29–5.09(m,1H) ,4.53(d,J=12.4Hz,1H),3.70(s,2H),3.64–3.45(m,6H),3.25–3.13(m,3H),3. 00(m,3H),2.83(m,1H),2.67–2.61(m,1H),2.41(s,3H),1.21(t,J=7.5Hz,3H).

[0473] Example 28: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 28)

[0474] Step 1: Synthesis of compound 28-1

[0475] 2,6-Dibromo-4-methoxypyridine (10.00 g) was dispersed in dioxane (200 mL). Tert-butyl carbamate (17.56 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (6.26 g), and cesium carbonate (73.06 g) were added at room temperature. After addition, the reaction mixture was incubated at 100°C under nitrogen for 14 hours. LCMS monitored the reaction completion. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (500 mL) and water (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to afford compound 28-1 (9.3 g).

[0476] Step 2: Synthesis of compound 28-2

[0477] Compound 28-1 (9.3 g) was dispersed in dichloromethane (100 mL). Trifluoroacetic acid (30.91 g) was added at 0°C. The reaction mixture was allowed to react at 25°C for 12 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated, and the residue was added with acetonitrile (50 mL) and water (40 mL) and lyophilized to afford compound 28-2 (11.0 g, crude product).

[0478] Step 3: Synthesis of compound 28-3

[0479] Methyl 4-amino-2,6-difluorobenzoate (1.78 g) was weighed and dispersed in 6M aqueous hydrogen chloride solution (5.2 mL). A solution of sodium nitrite (0.595 g) dissolved in water (8.62 mL) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Urea (51.79 mg) was then added to a solution of compound 28-2 (2.0 g, crude product, approximately 60% content) dissolved in water (40.0 mL). The mixture was allowed to react at room temperature for 1.5 h. A solution of sodium acetate (636.65 mg) in water (40 mL) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 5 h. The reaction was monitored by LCMS. The reaction mixture was filtered, and the filter cake was washed with water and dried to yield compound 28-3 (2.8 g).

[0480] Step 4: Synthesis of compound 28-4

[0481] Compound 28-3 (1.0 g) was dissolved in water (10.0 mL) and pyridine (20.0 mL), and anhydrous copper sulfate (2.37 g) was added. The mixture was then reacted at 100°C for 1 h. The reaction was completed. The reaction solution was diluted with water (40.0 mL) and extracted with ethyl acetate (50.0 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain compound 28-4 (300 mg).

[0482] Step 5: Synthesis of compound 28-5

[0483] Compound 28-4 (700 mg) was dispersed in a mixed solvent of acetonitrile (12 mL) and tetrahydrofuran (12 mL). Under nitrogen, tert-butyl nitrite (430.61 mg) was added dropwise at 0°C. The reaction mixture was allowed to react at 0°C for 0.5 hours. Cuprous bromide (1.2 g) was then added. After the addition, the reaction mixture was allowed to react at 80°C for 4 hours. Completion of the reaction was monitored by LCMS. Water and ethyl acetate were added to the reaction mixture for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 28-5 (360 mg) was obtained by column chromatography (dichloromethane / methanol = 99 / 1).

[0484] Step 6: Synthesis of compound 28-6

[0485] Compound 28-5 (360 mg) was dissolved in dioxane (10 mL). 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (208.36 mg), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium dichloromethane complex (110.48 mg), and potassium phosphate (574.34 mg) were added at room temperature. After addition, the reaction mixture was incubated at 90°C under nitrogen for 3 hours. LCMS monitoring of the reaction indicated completion. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 28-6 (240 mg).

[0486] Step 7: Synthesis of compound 28-7

[0487] Compound 28-6 (300 mg) was dissolved in tetrahydrofuran (15 mL) and methanol (15 mL). Pd / C (10%, 105.22 mg) was added. After addition, the atmosphere was replaced with hydrogen and protected. The reaction mixture was allowed to react at 25°C for 1 hour. LCMS monitored the reaction completion. The reaction mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 28-7 (260 mg).

[0488] Step 8: Synthesis of compound 28-8

[0489] Compound 28-7 (140 mg) was dispersed in acetonitrile (8 mL), and potassium iodide (667.23 mg) and trimethylsilyl chloride (665.01 mg) were added. The reaction mixture was allowed to react at 80°C for 10 hours. LCMS monitored the completion of the reaction. At 0°C, saturated aqueous sodium bicarbonate solution (5 mL) was added, followed by saturated aqueous sodium thiosulfate solution (5 mL), and extraction was performed with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (methanol / dichloromethane = 0-10%) to afford compound 28-8 (110 mg).

[0490] Step 9: Synthesis of compound 28-9

[0491] Compound 28-8 (115 mg) was dissolved in dichloromethane (10 mL). N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (120 mg) and N,N-diisopropylethylamine (213.32 mg) were added at room temperature. After addition, the reaction mixture was stirred at 30°C under nitrogen atmosphere for 16 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 28-9 (70 mg).

[0492] Step 10: Synthesis of compound 28-10

[0493] Compound 28-9 (50 mg) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, a solution of lithium aluminum tetrahydride in tetrahydrofuran (87.74 μL, 1 mol / L) was added dropwise at 0°C. The reaction mixture was allowed to react at 0°C for 0.5 hours. LCMS monitored the reaction completion. The reaction was quenched by the addition of water (0.1 mL) and dried over anhydrous sodium sulfate. The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (methanol / dichloromethane = 0-10%) to afford compound 28-10 (35 mg).

[0494] Step 11: Synthesis of compound 28-11

[0495] Compound 28-10 (20 mg) was dispersed in N,N-dimethylformamide (10 mL). N-bromosuccinimide (6.58 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 1 hour under nitrogen atmosphere. LCMS monitored the reaction completion. Water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 28-11 (25 mg, crude product).

[0496] Step 12: Synthesis of compound 28-12

[0497] Compound 28-11 (23 mg) was dispersed in acetonitrile (4 mL), and phosphorus tribromide (20 uL) was added at 0°C. The reaction mixture was allowed to react at 25°C for 1 hour. LCMS monitored the completion of the reaction. The reaction mixture was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 28-12 (25 mg).

[0498] Step 13: Synthesis of compound 28-13

[0499] Dimethylamine hydrochloride (9.54 mg) was dispersed in acetonitrile (4 mL). Potassium carbonate (16.17 mg) was added at room temperature. Compound 28-12 (16 mg) was then added. The reaction mixture was allowed to react at 60°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was filtered and concentrated to afford compound 28-13 (15 mg).

[0500] Step 14: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0501] Compound 28-13 (15 mg) was dissolved in dioxane (3 mL) and water (0.5 mL). Intermediate 22-14 (16 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (2.84 mg), and potassium phosphate (14.74 mg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 90°C under nitrogen protection for 4 hours. The reaction was monitored by LCMS. The reaction solution was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 75 / 25), and then purified by preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: 0.7% NH4HCO3 in H2O; B%: 65%, B is acetonitrile, 25 mL / min) to obtain 5.1 mg of the title compound.

[0502] LC-MS (ESI): m / z = 786.2 [M+H] +

[0503] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.43(s,1H),8.10–8.02(m,1H),7.97(d,J=2.0Hz ,1H),7.88(dd,J=7.8,2.6Hz,2H),7.70(dd,J=8.7,2.1Hz,1H),5.69(s,1H),5.56–5.26( m,3H),4.37(d,J=18.7Hz,1H),4.13(m,1H),3.99(s,1H),3.72–3.62(m,1H),3.54(s,2H) ,2.96–2.76(m,2H),2.75–2.62(m,2H),2.40(s,3H),2.17(s,6H),1.24(t,J=7.6Hz,3H).

[0504] Example 29: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 29)

[0505] Step 1: Synthesis of compound 29-1

[0506] Methyl 4-aminobenzoate (0.9 g) was weighed and dispersed in a 6 M aqueous solution of hydrogen chloride (2.5 mL). A solution of sodium nitrite (0.43 g) dissolved in water (2.8 mL) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Urea (31.9 mg) was then added to a solution of compound 28-2 (1 g) dissolved in water (20.0 mL). The mixture was allowed to react at room temperature for 1.5 h. A solution of sodium acetate (1.6 g) in water (20 mL) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 5 h. The reaction was monitored by LCMS. The reaction mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain compound 29-1 (1.2 g).

[0507] Step 2: Synthesis of compound 29-2

[0508] Compound 29-1 (1.2 g) was dispersed in dichloromethane (80 mL). Lead tetraacetate (3.5 g) was added at room temperature. The reaction mixture was allowed to react at 50°C for 1 hour. LCMS monitored the reaction completion. The reaction mixture was diluted with 300 mL of dichloromethane, stirred thoroughly, and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 29-2 (2.8 g, crude product).

[0509] Step 3: Synthesis of compound 29-3

[0510] Compound 29-2 (2.8 g) was dispersed in acetonitrile (100 mL) and, under nitrogen, tert-butyl nitrite (2.0 g) was added dropwise at 0°C. The reaction mixture was allowed to react at 0°C for 30 min, followed by the addition of cuprous bromide (3.8 g). After addition, the reaction mixture was allowed to react at 80°C for 1 hour. Completion of the reaction was monitored by LCMS. Water and ethyl acetate were added to the reaction mixture for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 99 / 1) to afford compound 29-3 (448 mg).

[0511] Step 4: Synthesis of compound 29-4

[0512] Compound 29-3 (448 mg) was dissolved in dioxane (30 mL) and water (3 mL). 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (353 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (125.9 mg), and potassium phosphate (729.7 mg) were added at room temperature. After addition, the reaction mixture was incubated at 90°C under nitrogen for 3 hours. LCMS monitoring of the reaction indicated completion. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 29-4 (251 mg).

[0513] Step 5: Synthesis of compound 29-5

[0514] Compound 29-4 (251 mg) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL). Pd / C (10%, 251 mg) was added. After addition, the atmosphere was replaced with hydrogen and protected. The reaction mixture was allowed to react at 25°C for 1 hour. LCMS monitored the reaction completion. The reaction mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 29-5 (247 mg).

[0515] Step 6: Synthesis of compound 29-6

[0516] Compound 29-5 (247 mg) was dissolved in tetrahydrofuran (20 mL). Under nitrogen, a solution of lithium aluminum tetrahydride in tetrahydrofuran (54.0 mg, 1 mol / L) was added dropwise at 0°C. The reaction mixture was allowed to react at 0°C for 1 hour. LCMS monitored the reaction completion. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 29-6 (258 mg, crude product).

[0517] Step 7: Synthesis of compound 29-7

[0518] Compound 29-6 (258 mg) was dispersed in a hydrogen bromide and acetic acid solution (4 mL). After addition, the reaction mixture was reacted at 90°C for 16 hours. LCMS monitored the completion of the reaction. The reaction mixture was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 29-7 (179 mg).

[0519] Step 8: Synthesis of compound 29-8

[0520] 3,3-Difluoroazetidine hydrochloride (347.9 mg) was dispersed in acetonitrile (10 mL). Potassium carbonate (484 mg) was added at room temperature. The reaction mixture was stirred at 25°C for 0.5 hours. Compound 29-7 (179 mg) was then added. The reaction mixture was allowed to react at 60°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was filtered and purified by column chromatography (dichloromethane / methanol = 95 / 5) to afford compound 29-8 (105 mg).

[0521] Step 9: Synthesis of compound 29-9

[0522] Compound 29-8 (105 mg) was dispersed in acetonitrile (10 mL), and N-bromosuccinimide (64.9 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 2 hours under nitrogen atmosphere. LCMS monitored the reaction completion. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 29-9 (132 mg, crude product).

[0523] Step 10: Synthesis of compound 29-10

[0524] Compound 29-9 (120 mg) was dissolved in dichloromethane (10 mL). N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (113 mg) and N,N-diisopropylethylamine (73.1 mg) were added at room temperature. After addition, the reaction mixture was stirred at 25°C under nitrogen atmosphere for 16 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 29-10 (81.4 mg, crude product).

[0525] Step 11: Synthesis of compound 29-11

[0526] Compound 29-10 (53.4 mg) was dissolved in N-methylpyrrolidone (1 mL), and piperazine (139.42 mg) was added. After addition, the reaction mixture was microwaved at 140°C under nitrogen atmosphere for 1.5 hours. LCMS monitored the reaction completion. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 29-11 (51.3 mg, crude product).

[0527] Step 12: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0528] Compound 29-11 (51.3 mg) was dissolved in N,N-dimethylformamide (2 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (17.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 mg), and 1-hydroxybenzotriazole (2.1 mg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 65%, B is acetonitrile, 25 mL / min) to obtain 2.5 mg of the title compound.

[0529] LC-MS (ESI): m / z = 801.2 [M+H] +

[0530] 1H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 8.08 (m, 3H), 7.96 (d, J = 2.1Hz, 1H), 7.70 (dd, J = 8.7, 2.1Hz ,1H),7.55(d,J=8.6Hz,2H),5.37(s,2H),4.51(d,J=12.3Hz,1H),3.81(s,2H),3.72(s,1H),3.6 3(m,4H),3.50(d,J=11.6Hz,1H),3.22(s,1H),3.03(d,J=7.6Hz,2H),2.93(d,J=11.0Hz,1H),2. 76(d,J=11.4Hz,1H),2.70-2.64(m,1H),2.40(s,3H),2.35-2.30(m,1H),1.20(d,J=7.4Hz,3H).

[0531] Example 30: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 30)

[0532] Step 1: Synthesis of compound 30-2

[0533] Compound 22-13 (70.0 mg) and compound 30-1 (50.5 mg) were dissolved in dioxane (0.8 mL) and water (0.2 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.9 mg) and potassium phosphate (88.4 mg) were added, and the mixture was reacted at 90°C under nitrogen for 1 h. After completion of the reaction, the reaction solution was directly concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 30-2 (50.0 mg).

[0534] Step 2: Synthesis of compound 30-3

[0535] Compound 30-2 (40.0 mg) was dissolved in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) and allowed to react at room temperature for 30 min. After completion of the reaction, the reaction solution was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 30-3 (50.0 mg, crude product).

[0536] Step 3: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0537] Compound 30-3 (50 mg) and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (22.4 mg) were dissolved in N,N-dimethylformamide (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41.8 mg) and 1-hydroxybenzotriazole (0.98 mg) were added, and the mixture was reacted at 45°C for 12 h. After the reaction, the reaction solution was preparatively eluted (chromatographic column: YMC TA column; mobile phase: A: 7 mmol NH4HCO3 aqueous solution; B: acetonitrile, B%: 30% to 60%, 40 mL / min) to obtain 21.0 mg of the title compound.

[0538] LC-MS (ESI): m / z = 824.3 [M+H] + ;

[0539] 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.59-8.43(m,1H),8.10-8.03(m,1H),8.03-7.86( m,3H),7.76-7.62(m,2H),5.73-5.56(m,1H),5.54-5.41(m,1H),5.37-5.26(m,1H),4.97( s,1H),4.37-4.11(m,1H),3.69-3.47(m,7H),3.19-3.03(m,1H),2.89-2.77(m,1H),2.75- 2.59(m,2H),2.46-2.35(m,6H),2.29-2.14(m,1H),1.39-1.26(m,3H),1.25-1.14(m,3H).

[0540] Example 31: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(3-(5-hydroxy-6-methylpyrimidine)-4-carbonyl)-3-azabicyclo[4.1.0]heptane-6-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 31)

[0541] Step 1: Synthesis of compound 31-2

[0542] The starting material 31-1 (97.5 mg) and compound 22-13 (120.0 mg) were dissolved in water (0.2 mL) and toluene (1.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (28.9 mg) and cesium carbonate (116.4 mg) were added. The mixture was then microwaved under nitrogen at 110°C for 50 min. The reaction was complete. The reaction solution was directly concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain compound 31-2 (70.0 mg).

[0543] Step 2: Synthesis of compound 31-3

[0544] Compound 31-2 (80.0 mg) was dissolved in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) and allowed to react at room temperature for 30 min. The reaction was complete. The reaction solution was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 31-3 (120 mg, crude product).

[0545] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(3-(5-hydroxy-6-methylpyrimidine)-4-carbonyl)-3-azabicyclo[4.1.0]heptane-6-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0546] Compound 31-3 (90.0 mg) and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (28.2 mg) were dissolved in N,N-dimethylformamide (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75.2 mg) and 1-hydroxybenzotriazole (1.8 mg) were added and allowed to react at room temperature for 2 h. After the reaction, the reaction solution was preparatively eluted (chromatographic column: YMC TA column; mobile phase: A: 7 mmol NH4HCO3 aqueous solution; B: acetonitrile, B%: 40% to 70%, 40 mL / min) to obtain 21.0 mg of the title compound.

[0547] LC-MS (ESI): m / z = 824.2 [M+H] + ;

[0548] 1H NMR(400MHz,DMSO-d6)δ10.48-10.40(m,1H),10.26-10.17(m,1H),8.61-8.51(m,1H),8.14-8.01(m,2H),7.99-7 .94(m,1H),7.93-7.77(m,1H),7.73-7.67(m,1H),5.43-5.30(m,2H),4.59-4.35(m,2H),4.11-3.93(m,2H),3.92 -3.75(m,2H),3.73-3.52(m,4H),3.30-3.26(m,1H),3.25-3.13(m,2H),3.11-2.89(m,2H),2.82-2.72(m,1H),2. 56-2.53(m,3H),2.47-2.39(m,3H),2.21-2.10(m,1H),2.05-1.93(m,1H),1.84-1.67(m,1H),1.37-1.19(m,3H).

[0549] Example 32: Synthesis of 2-(2-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 32)

[0550] Step 1: Synthesis of compound 32-1

[0551] Methyl 4-amino-2-fluorobenzoate (5 g) and methoxymethylamine (5.77 g) were dispersed in tetrahydrofuran (80 mL) and protected by nitrogen. Isopropylmagnesium chloride (1.3 M, 136.43 mL) was slowly added dropwise at -20 ° C. The reaction was continued to stir at low temperature for 4 hours. Saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane (200 mL). The liquids were separated, the organic phase was concentrated, and the mixture was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 32-1 (5 g).

[0552] Step 2: Synthesis of compound 32-2

[0553] Compound 32-1 (1.42 g) was dissolved in a 6M aqueous hydrochloric acid solution (15 mL). A solution of sodium nitrite (545 mg) dissolved in water (3 mL) was added dropwise at 0°C. The mixture was reacted at 0°C for 30 minutes. Urea (89 mg) was then added to consume the excess sodium nitrite. The above solution was then added to a solution of compound 28-2 (2 g) dissolved in water (15 mL) and reacted at room temperature for 1.5 hours. A solution of sodium acetate (10.78 g) in water (100 mL) was then added dropwise. The mixture was stirred at room temperature for 12 hours, extracted with dichloromethane (200 mL*2), separated, and the organic phase was concentrated. Compound 32-2 (2.5 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0554] Step 3: Synthesis of compound 32-3

[0555] Compound 32-2 (2.5 g) and lead tetraacetate (4.77 g) were dispersed in dichloromethane (50 mL) and stirred at 50° C. under nitrogen protection for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to about 9. The mixture was extracted with dichloromethane, separated, and the organic phase was concentrated. Compound 32-3 (2.4 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0556] Step 4: Synthesis of compound 32-4

[0557] Compound 32-3 (2 g) was dispersed in acetonitrile (40 mL) and protected by nitrogen. Tert-butyl nitrite (1.49 g) and cuprous bromide (4.14 g) were added under ice-bath conditions. The temperature was raised to 80° C. and stirred for 1 hour. The mixture was filtered and the filtrate was directly concentrated. Compound 32-4 (900 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0558] Step 5: Synthesis of compound 32-5

[0559] Compound 32-4 (900 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (676 mg), potassium phosphate (1.86 g) and Pd(dppf)Cl2 (240 mg) were dispersed in dioxane (40 mL) / water (10 mL) and protected by nitrogen. The reaction was stirred at 90°C for 6 hours. LCMS showed that the substrate was completely converted. Water (60 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate. The layers were separated, the organic phase was concentrated, and the mixture was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 32-5 (500 mg).

[0560] Step 6: Synthesis of compound 32-6

[0561] Compound 32-5 (400 mg) was dispersed in tetrahydrofuran (4 mL) / methanol (10 mL), and then palladium / carbon (10%, 129 mg) was added, and hydrogen was replaced three times. The reaction was stirred under hydrogen balloon pressure for 1 hour, filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 32-6 (400 mg).

[0562] Step 7: Synthesis of compound 32-7

[0563] Compound 32-6 (250 mg) was weighed and dissolved in acetonitrile (20 mL). Trimethylsilyl chloride (1.07 g) and potassium iodide (1.15 g) were added and stirred at 80°C for 1 hour. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to weak alkaline. The iodine was quenched with saturated anhydrous sodium sulfite solution, extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 32-7 (230 mg).

[0564] Step 8: Synthesis of compound 32-8

[0565] Compound 32-7 (240 mg) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection, and diisobutylaluminum hydride (1 M, 4.86 mL) was slowly added dropwise at -20 ° C. Saturated ammonium chloride solution (4 mL) and water (10 mL) were slowly added dropwise at -20 ° C to quench the reaction. Then, the reaction was stirred at room temperature for 1 hour, filtered, and the filter cake was redissolved in a mixed solvent of dichloromethane / methanol (10 / 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 32-8 (190 mg).

[0566] Step 9: Synthesis of compound 32-9

[0567] Compound 32-8 (200 mg) was dissolved in acetonitrile (10 mL), and then N-bromosuccinimide (124 mg) was added. The reaction was stirred at 25°C for 1 hour. LCMS showed that the substrate was completely converted. Water (40 ml) was added for dilution and filtered. The filter cake was redissolved in dichloromethane / methanol (10 / 1) solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 32-9 (250 mg).

[0568] Step 10: Synthesis of compound 32-10

[0569] Compound 32-9 (250 mg) and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodo-acetamide (249 mg) were dissolved in dichloromethane (8 mL), and then N,N-diisopropylethylamine (265 mg, 357.75 μL) was added. Under nitrogen protection, the reaction was stirred at 25°C for 12 hours. The solvent was concentrated under reduced pressure and column chromatography (dichloromethane / methanol = 20 / 1) was used to obtain compound 32-10 (140 mg).

[0570] Step 11: Synthesis of compound 32-11

[0571] Azetidine hydrochloride (31 mg) was dispersed in tetrahydrofuran (2 mL), and triethylamine (70 mg) was added. The mixture was stirred at 30°C for 30 minutes, and then compound 32-10 (50 mg), acetic acid (60 mg) and sodium cyanoborohydride (36 mg) were added. The mixture was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to a weak base, and the mixture was extracted with dichloromethane. The liquid was separated, and the organic phase was concentrated and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 32-11 (50 mg).

[0572] Step 12: Synthesis of 2-(2-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0573] Compound 32-11 (25 mg), compound 22-14 (27 mg), potassium phosphate (33 mg) and Pd(dppf)Cl2 (6 mg) were dispersed in water (1 mL) / dioxane (3 mL) and stirred at 90°C under nitrogen for 3 hours. The solvent was directly concentrated to prepare (chromatographic column: YMC C18; mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 30% to 70%, B is acetonitrile, 25 mL / min) to obtain 9 mg of the title compound.

[0574] LC-MS (ESI): m / z = 780.2 [M+H] +

[0575] 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.48(s,1H),8.17–7.83(m,4H),7.70(dd,J=8. 8,2.1Hz,1H),7.66–7.56(m,1H),5.68(s,1H),5.49–5.26(m,2H),4.43–4.32(m,1H),4 .19–3.94(m,2H),3.60(s,2H),3.53–3.43(m,2H),3.18(m,4H),2.90–2.77(m,1H),2.7 4–2.62(m,1H),2.42(s,3H),2.20–2.06(m,1H),2.04–1.94(m,2H),1.29–1.14(m,3H).

[0576] Example 33: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 33)

[0577] Step 1: Synthesis of compound 33-1

[0578] Tetrahydropyrrole (26 mg) was dispersed in tetrahydrofuran (2 mL), followed by the addition of compound 32-10 (55 mg), acetic acid (23 mg), and sodium cyanoborohydride (44 mg). The mixture was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to a weak base, and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford compound 33-1 (50 mg).

[0579] Step 2: Synthesis of compound 33-2

[0580] Compound 33-1 (40 mg) and piperazine (105 mg) were dissolved in N-methylpyrrolidone (2 mL) and stirred in a microwave at 140° C. for 1 hour under nitrogen protection. LCMS showed that the substrate was completely converted. The mixture was diluted with water (4 mL) and extracted twice with ethyl acetate. The mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 33-2 (40 mg).

[0581] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0582] Compound 33-2 (40 mg), 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (19 mg), 1-hydroxybenzotriazole (2.45 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.99 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 25°C under nitrogen for 12 hours. After the reaction, the reaction solution was directly prepared (chromatographic column: YMC C18; mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 30% to 70%, B is acetonitrile, 25 mL / min) to obtain 8.6 mg of the title compound.

[0583] LC-MS (ESI): m / z = 797.2 [M+H] +

[0584] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.49(s,1H),8.06(d,J=8.6Hz,1H),7.96(m,2H),7.91 (dd,J=10.5,2.2Hz,1H),7.73–7.62(m,2H),5.38(s,2H),4.51(d,J=12.3Hz,1H),3.74–3.64( m,4H),3.51–3.46(m,2H),3.24–3.18(m,2H),3.07–2.96(m,3H),2.77(d,J=11.3Hz,1H),2.59 (d,J=11.2Hz,1H),2.48–2.46(m,2H),2.42(s,3H),1.74–1.67(m,4H),1.21(t,J=7.4Hz,3H).

[0585] Example 34: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 34)

[0586] Step 1: Synthesis of compound 34-1

[0587] Dimethylamine hydrochloride (30 mg) was dissolved in acetonitrile (2 mL), and triethylamine (55.6 mg) was added. The reaction mixture was stirred at room temperature for 30 min. Acetic acid (54.9 mg), compound 32-10 (55 mg), and sodium cyanoborohydride (34.5 mg) were then added sequentially. After addition, the reaction mixture was allowed to react at 25°C for 1 hour. Completion of the reaction was monitored by LCMS. The reaction mixture was purified by column chromatography (dichloromethane / methanol = 96 / 4) to afford compound 34-1 (21 mg).

[0588] Step 2: Synthesis of compound 34-2

[0589] Compound 34-1 (21 mg) was dissolved in N-methylpyrrolidone (1 mL), and piperazine (59.1 mg) was added. After addition, the reaction mixture was microwaved at 140°C under nitrogen atmosphere for 1.5 hours. LCMS monitored the reaction completion. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 34-2 (20 mg, crude product).

[0590] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0591] Compound 34-2 (20 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (9.7 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 mg), and 1-hydroxybenzotriazole (851 μg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.5% NH4OH in H2O; B%: 60%, B is acetonitrile, 25 mL / min) to obtain 8.1 mg of the title compound.

[0592] LC-MS (ESI): m / z = 771.2 [M+H] +

[0593] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.42(s,1H),8.06(d,J=8.5Hz,1H),7.97(dd,J=8.2,2.2Hz,2H) ,7.92(dd,J=10.5,2.2Hz,1H),7.70(dd,J=8.9,2.1Hz,1H),7.65(t,J=8.1Hz,1H),5.38(s,2H),4.51( d,J=12.4Hz,1H),3.69(m,2H),3.50(s,3H),3.03(d,J=7.7Hz,2H),2.94(m,1H),2.76(d,J=11.2Hz,1H ),2.68-2.67(m,1H),2.60-2.57(m,1H),2.39(s,3H),2.33(m,1H),2.18(s,6H),1.21(t,J=7.5Hz,3H).

[0594] Example 35: Synthesis of 2-(2-(4-(bis(methyl-d3)amino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 35)

[0595] Step 1. Synthesis of compound 35-1

[0596] Compound 35-3 (131 mg) was dispersed in tetrahydrofuran (6 mL), followed by the addition of triethylamine (242 mg). The mixture was stirred at 25°C for 30 minutes, followed by the addition of 32-10 (180 mg), acetic acid (180 mg), and sodium cyanoborohydride (149 mg). The reaction was stirred at 30°C for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to a weakly alkaline state, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford the title compound 35-1 (125 mg).

[0597] Step 2: Synthesis of Compound 35-2

[0598] Compound 35-1 (100 mg) and piperazine (271 mg) were dissolved in N-methylpyrrolidone (3 mL) and stirred in a microwave at 140°C under nitrogen protection for 1 hour. LCMS showed that the substrate was completely converted. The mixture was diluted with water (8 mL) and extracted twice with ethyl acetate. The mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 35-2 (100 mg).

[0599] Step 3. Synthesis of 2-(2-(4-(bis(methyl-d3)amino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0600] Compound 35-2 (100 mg), 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (48 mg), 1-hydroxybenzotriazole (6 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at 25°C under nitrogen for 12 hours. After the reaction, the reaction solution was directly purified (chromatographic column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-70%, B: acetonitrile, 25 mL / min) to obtain the title compound (40 mg, 33% yield). LC-MS (ESI): m / z = 777.2 [M+H] +

[0601] 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.24(s,1H),9.83(s,1H),8.58(s,1H),8.15–8.10(m,1H),8.1 0–8.06(m,1H),7.98(d,J=2.2Hz,1H),7.85(t,J=8.1Hz,1H),7.71(dd,J=8.9,2.1Hz,1H),5.40(s,2H) ,4.52(d,J=12.5Hz,1H),4.42(s,2H),3.74–3.67(m,2H),3.51–3.45(m,2H),3.29–3.19(m,1H),3.07– 2.92(m,3H),2.78(d,J=11.1Hz,1H),2.61(d,J=11.0Hz,1H),2.45–2.44(m,2H),1.22(t,J=7.4Hz,3H).

[0602] Example 36: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 36)

[0603] Dissolve the starting material, 3-methoxyazetidine hydrochloride (80 mg), in tetrahydrofuran. Add triethylamine (99 mg, 135.33 μL) and stir for 30 minutes. Then add acetic acid (73 mg), intermediate 38-4 (60 mg), and sodium cyanoborohydride (50.94 mg). Allow to react at room temperature for 1 hour, and monitor the reaction completion using LMCS. Add 20 mL of water to the system, extract with 40 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the product by reverse-phase HPLC (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile. B%: 35% to 65% over 8.7 min, gradient: 55%, RT: 8.7, 25 mL / min), and lyophilize. 7.5 mg of the title compound was obtained.

[0604] LC-MS (ESI): m / z = 813.2 [M+H] +

[0605] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.57(s,1H),8.07(d,J=8.5Hz,1H),8.00 –7.84(m,3H),7.70(m,1H),7.62(t,J=8.1Hz,1H),5.38(s,2H),4.52(d,J=12.4H z,1H),3.98(m,1H),3.69(m,4H),3.52(m,3H),3.22(m,1H),3.14(s,3H),3.08–2 .88(m,5H),2.78(m,1H),2.64–2.57(m,1H),2.44(s,3H),1.22(t,J=7.4Hz,3H).

[0606] Example 37: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3-(difluoromethoxy)azetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 37)

[0607] Step 1: Synthesis of compound 37-1

[0608] 3-(Difluoromethoxy)azetidine (118.2 mg) was dispersed in acetonitrile (10 mL). Potassium carbonate (132.5 mg) and compound 29-7 (160 mg) were added at room temperature. After addition, the reaction mixture was incubated at 60°C for 2 hours. LCMS monitoring of the reaction completion was performed. The reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 95 / 5) to afford compound 37-1 (123.9 mg).

[0609] Step 2: Synthesis of compound 37-2

[0610] Compound 37-1 (124 mg) was dispersed in acetonitrile (10 mL), and N-bromosuccinimide (71.1 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 1 hour under nitrogen atmosphere. LCMS monitored the reaction completion. Water (5 mL) was added to the reaction mixture, which was concentrated and purified by column chromatography (dichloromethane / methanol = 90 / 10) to afford compound 37-2 (129 mg).

[0611] Step 3: Synthesis of compound 37-3

[0612] Compound 37-2 (129 mg) was dissolved in dichloromethane (5 mL). N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (113.5 mg) and N,N-diisopropylethylamine (73.4 mg) were added at room temperature. After addition, the reaction mixture was stirred at 25°C under nitrogen atmosphere for 16 hours. LCMS monitoring of the reaction completion was performed. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 37-3 (115 mg).

[0613] Step 4: Synthesis of compound 37-4

[0614] Compound 37-3 (98 mg) was dissolved in N-methylpyrrolidone (1 mL), and piperazine (299.6 mg) was added. After addition, the reaction mixture was microwaved at 140°C under nitrogen atmosphere for 1 hour. LCMS monitored the reaction completion. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 37-4 (120.9 mg, crude product).

[0615] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3-(difluoromethoxy)azetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0616] Compound 37-4 (120.9 mg) was dissolved in N,N-dimethylformamide (2 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (28.7 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.7 mg), and 1-hydroxybenzotriazole (2.3 mg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: 0.7% NH4HCO3 in H2O; B%: 65%, B is acetonitrile, 25 mL / min) to give 12 mg of the title compound.

[0617] LC-MS (ESI): m / z = 831.2 [M+H] +

[0618] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.48(s,1H),8.07(dd,J=8.6,3.2Hz,3H),7.96(d,J=2.0 Hz,1H),7.70(dd,J=8.8,2.1Hz,1H),7.51(d,J=8.5Hz,2H),6.76(m,1H),5.37(s,2H),4.72(t,J =5.9Hz,1H),4.51(d,J=12.4Hz,1H),3.70(d,J=13.8Hz,4H),3.57(m,2H),3.51(s,1H),3.11-2 .88(m,6H),2.76(d,J=11.1Hz,1H),2.59(d,J=11.3Hz,1H),2.42(s,3H),1.21(t,J=7.5Hz,3H).

[0619] Example 38: Synthesis of 2-(2-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 38)

[0620] Step 1: Synthesis of compound 38-1

[0621] Compound 32-10 (250 mg) and p-toluenesulfonic acid (21 mg) were dissolved in toluene (8 mL), and ethylene glycol (207 mg) was added. The mixture was stirred at 100°C under nitrogen for 2 hours. The solvent was directly concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 38-1 (240 mg).

[0622] Step 2: Synthesis of compound 38-2

[0623] Piperazine (614 mg) and compound 38-1 (230 mg) were dissolved in N-methylpyrrolidone (4 mL) and stirred in a microwave at 140° C. for 1 hour under nitrogen protection. LCMS showed that the substrate was completely converted. The mixture was diluted with water (20 mL) and extracted with ethyl acetate three times. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound 38-2 (230 mg).

[0624] Step 3: Synthesis of compound 38-3

[0625] Compound 38-2 (230 mg), 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (98 mg), 1-hydroxybenzotriazole (14 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134 mg) were dissolved in N,N-dimethylformamide (5 mL) and protected by nitrogen. The mixture was stirred at 25°C for 12 hours, diluted with water (20 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 38-3 (240 mg).

[0626] Step 4: Synthesis of compound 38-4

[0627] Compound 38-3 (200 mg) was dissolved in dilute hydrochloric acid solution (2M, 5 mL) and tetrahydrofuran (8 mL), stirred and reacted at 55°C for 24 hours, saturated sodium bicarbonate solution was added to adjust the pH to close to neutral, extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 38-4 (180 mg).

[0628] Step 5: Synthesis of 2-(2-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0629] Azetidine hydrochloride (40 mg) was dispersed in tetrahydrofuran (2 mL), followed by the addition of triethylamine (54 mg). The mixture was stirred at 25°C for 30 minutes, followed by the addition of compound 38-4 (40 mg), sodium cyanoborohydride (33 mg), and acetic acid (48 mg). The reaction was stirred at 25°C for 1 hour. Water (5 mL) was added for dilution, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatographic column: YMC C18; mobile phase: 0.7% NH4HCO3 in H2O; B%: 30% to 70%, with B being acetonitrile, at 25 mL / min) afforded 5 mg of the title compound.

[0630] LC-MS (ESI): m / z = 783.2 [M+H] +

[0631] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.51(s,1H),8.06(d,J=8.6Hz,1H),7.98–7.83(m,3H),7.70(d d,J=8.9,2.1Hz,1H),7.65–7.57(m,1H),5.38(s,2H),4.51(d,J=12.4Hz,1H),3.71(d,J=12.9Hz,3H), 3.61(s,2H),3.50(d,J=12.6Hz,1H),3.21–3.14(m,4H),3.07–2.97(m,2H),2.94(d,J=11.6Hz,1H),2 .77(d,J=11.4Hz,1H),2.60(d,J=10.8Hz,1H),2.43(s,3H),2.05–1.92(m,2H),1.21(t,J=7.5Hz,3H).

[0632] Example 39: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-(fluoromethyl)azetidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 39)

[0633] Step 1: Synthesis of compound 39-1

[0634] 3-(Fluoromethyl)azetidine hydrochloride (301.5 mg) was dispersed in acetonitrile (10 mL). Potassium carbonate (397.6 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 0.5 hours. Compound 29-7 (160 mg) was then added. After addition, the reaction mixture was allowed to react at 60°C for 2 hours. LCMS monitoring of the reaction completion was performed. The reaction mixture was filtered and purified by column chromatography (dichloromethane / methanol = 95 / 5) to afford compound 39-1 (124 mg).

[0635] Step 2: Synthesis of compound 39-2

[0636] Compound 39-1 (124 mg) was dispersed in acetonitrile (10 mL), and N-bromosuccinimide (71.1 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 1 hour under nitrogen atmosphere. Completion of the reaction was monitored by LCMS. Water (5 mL) was added to the reaction mixture, which was then concentrated and purified by column chromatography (dichloromethane / methanol = 90 / 10) to afford compound 39-2 (123 mg).

[0637] Step 3: Synthesis of compound 39-3

[0638] Compound 39-2 (123 mg) was dissolved in dichloromethane (10 mL). N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (117 mg) and N,N-diisopropylethylamine (75.6 mg) were added at room temperature. After addition, the reaction mixture was stirred at 25°C under nitrogen atmosphere for 16 hours. LCMS monitoring of the reaction completion was performed. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 39-3 (98 mg).

[0639] Step 4: Synthesis of compound 39-4

[0640] Compound 39-3 (98 mg) was dissolved in N-methylpyrrolidone (1 mL), and piperazine (244.2 mg) was added. After addition, the reaction mixture was microwaved at 140°C under nitrogen atmosphere for 1 hour. LCMS monitored the reaction completion. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 39-4 (93.7 mg, crude product).

[0641] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-(fluoromethyl)azetidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0642] Compound 39-4 (93.7 mg) was dissolved in N,N-dimethylformamide (2 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (32.3 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.2 mg), and 1-hydroxybenzotriazole (1.9 mg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: 0.7% NH4HCO3 in H2O; B%: 65%, B is acetonitrile, 25 mL / min) to give 6.7 mg of the title compound.

[0643] LC-MS (ESI): m / z = 797.3 [M+H] +

[0644] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.38(s,1H),8.06(m,3H),7.96(d,J=2.1Hz,1H),7 .69(dd,J=8.7,2.2Hz,1H),7.50(d,J=8.4Hz,2H),5.37(s,2H),4.58(d,J=6.1Hz,1H),4.4 9(dd,J=16.8,9.3Hz,2H),3.70(d,J=12.5Hz,2H),3.62(s,2H),3.49(d,J=12.3Hz,2H),3. 08-2.89(m,6H),2.76(m,2H),2.58(d,J=11.0Hz,2H),2.38(s,3H),1.21(t,J=7.8Hz,3H).

[0645] Example 40: Synthesis of 2-(2-(4-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 40)

[0646] Dissolve the raw material (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (88 mg) in tetrahydrofuran (5 mL), add triethylamine (99 mg, 135.33 μL), and stir for 30 minutes. Then add acetic acid (72.77 mg), intermediate 38-4 (60 mg), and sodium cyanoborohydride (50.13 mg). React at room temperature for 1 hour, and monitor the reaction completion by LCMS. Add 20 mL of water to the system, extract with 40 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. The product was sent for preparation and purified by reverse-phase high performance liquid chromatography (chromatographic column: YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase: A is 7 mmol / L aqueous ammonium bicarbonate solution; B is acetonitrile. B%: 35%-65% in 9 min, peak gradient: 57%, RT: 8.5 min. 25 mL / min), and lyophilized to obtain 7 mg of the title compound.

[0647] LC-MS (ESI): m / z = 825.3 [M+H] +

[0648] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.55(s,1H),8.07(d,J=8.6Hz,1H),7.97(m,2H),7.9 1(m,1H),7.75–7.68(m,2H),5.38(s,2H),4.52(d,J=12.3Hz,1H),4.37(s,1H),3.93(d,J=7 .6Hz,1H),3.87–3.63(m,5H),3.55(m,1H),3.50(m,2H),3.25–3.20(m,1H),3.01(m,3H),2. 81–2.74(m,2H),2.60(m,1H),2.44(s,3H),1.82(m,1H),1.61(m,1H),1.23(d,J=7.3Hz,3H).

[0649] Example 41: Synthesis of 2-(2-(4-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 41)

[0650] Using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride as the starting material, 8.5 mg of the title compound was obtained according to the synthesis method of Example 40. LC-MS (ESI): m / z = 825.3 [M+H] +

[0651] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.51(s,1H),8.06(d,J=8.6Hz,1H),7.99–7.94(m,2H),7.90(dd,J=10.6,2.2Hz, 1H),7.75–7.67(m,2H),5.38(s,2H),4.51(d,J=12.3Hz,1H),4.38–4.32(m,1H),3.93(d,J=7.6Hz,1H),3.87–3.78(m,2H ),3.75–3.64(m,2H),3.55(dd,J=7.6,1.8Hz,1H),3.52–3.47(m,2H),3.22–3.20(m,2H),3.06–2.91(m,3H),2.81–2.73 (m,2H),2.60(d,J=10.9Hz,1H),2.43(s,3H),1.82(dd,J=9.7,2.2Hz,1H),1.61(d,J=9.8Hz,1H),1.22(t,J=7.4Hz,3H).

[0652] Example 42: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3-cyanoazetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 42)

[0653] Step 1: Synthesis of compound 42-1

[0654] 3-Cyanocyclobutanamine hydrochloride (492.8 mg) was dispersed in acetonitrile (10 mL). Potassium carbonate (803.1 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 0.5 hours. Compound 29-7 (277 mg) was then added. After addition, the reaction mixture was allowed to react at 60°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was filtered and purified by column chromatography (dichloromethane / methanol = 95 / 5) to afford compound 42-1 (239.8 mg).

[0655] Step 2: Synthesis of compound 42-2

[0656] Compound 42-1 (239.8 mg) was dispersed in acetonitrile (10 mL). N-bromosuccinimide (140.4 mg) was added at room temperature. After addition, the reaction mixture was stirred at 25°C for 1 hour under nitrogen atmosphere. LCMS monitored the reaction completion. Water (5 mL) was added to the reaction mixture, which was then concentrated and purified by column chromatography (dichloromethane / methanol = 90 / 10) to afford compound 42-2 (320 mg, crude product).

[0657] Step 3: Synthesis of compound 42-3

[0658] Compound 42-2 (320 mg) was dissolved in dichloromethane (10 mL). N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (309.6 mg) and N,N-diisopropylethylamine (200.1 mg) were added at room temperature. After addition, the reaction mixture was stirred at 25°C under nitrogen atmosphere for 16 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25) to afford compound 42-3 (244 mg).

[0659] Step 4: Synthesis of compound 42-4

[0660] Compound 42-3 (244 mg) was dissolved in N-methylpyrrolidone (1.5 mL), and piperazine (647.8 mg) was added. After addition, the reaction mixture was microwaved at 140°C for 30 minutes under nitrogen atmosphere. LCMS monitored the reaction completion. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 42-4 (245 mg, crude product).

[0661] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((3-cyanoazetidin-1-yl)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0662] Compound 42-4 (245 mg) was dissolved in N,N-dimethylformamide (2 mL), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (63.5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107.7 mg), and 1-hydroxybenzotriazole (5.1 mg) were added at room temperature. After the addition was complete, the reaction solution was reacted at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: 0.7% NH4HCO3 in H2O; B%: 50%, B is acetonitrile, 25 mL / min) to give 28 mg of the title compound.

[0663] LC-MS (ESI): m / z = 790.2 [M+H] +

[0664] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.53(s,1H),8.07(dd,J=8.7,5.0Hz,3H),7.96(d,J=2.0 Hz,1H),7.70(dd,J=8.8,2.1Hz,1H),7.54-7.47(m,2H),5.38(s,2H),4.51(d,J=12.3Hz,1H),3 .80-3.68(m,2H),3.66(s,2H),3.55-3.43(m,6H),3.22(d,J=11.5Hz,1H),3.02(m,2H),2.98-2 .89(m,1H),2.77(d,J=11.4Hz,1H),2.60(d,J=11.1Hz,1H),2.43(s,3H),1.21(t,J=7.4Hz,3H).

[0665] Example 43: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2,5-difluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 43)

[0666] Step 1: Synthesis of compound 43-1

[0667] The raw material, methyl 4-amino-2,5-difluorobenzoate (5.0 g), was dissolved in tetrahydrofuran (150 mL). N-methoxymethylamine (3.26 g) was added. Under argon, the temperature was lowered to -20°C, and isopropylmagnesium chloride-lithium chloride (23.24 g) was added dropwise. The reaction was allowed to react at -20°C for 10 hours, and the reaction was monitored by LCMS. The system was quenched with saturated aqueous ammonium chloride. 50 mL of water was added to the system, and the mixture was extracted with 250 mL of dichloromethane. The layers were separated, and the organic phase was washed once with saturated aqueous sodium chloride. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography using dichloromethane:methanol = 80:1 was performed to obtain compound 43-1 (4.54 g).

[0668] Step 2: Synthesis of compound 43-2

[0669] Compound 43-1 (2.91 g) was dissolved in water (200 mL) and placed on an ice bath. Hydrochloric acid (6 M, 7.35 mL) and sodium nitrite (846 mg) were added at 0°C and stirred for 30 minutes. Urea (74 mg) was added and stirred for 10 minutes. 4-Methoxypyridine-2,6-diamine trifluoroacetate (4.50 g) was added and stirred at room temperature for 2 hours. Sodium acetate (3.62 g) was added. The reaction was allowed to react at room temperature for 5 hours, and the reaction was monitored for completion using LMCS. The system was adjusted to alkaline and extracted with 200 mL of dichloromethane. The layers were separated and the organic phase was washed once with a saturated sodium chloride solution. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 43-2 (4.44 g).

[0670] Step 3: Synthesis of compound 43-3

[0671] Dissolve compound 43-2 (4.44 g) in dichloromethane (20 mL) and add lead tetraacetate (8.06 g). Heat to 55°C. Allow to react for 2 hours. Completion of the reaction was monitored by LCMS. Filter through Celite, wash the filter cake with 100 mL of dichloromethane, spin-dry, and perform column chromatography using a 50:1 ratio of dichloromethane to methanol to obtain compound 43-3 (2.90 g).

[0672] Step 4: Synthesis of compound 43-4

[0673] Compound 43-3 (2.80 g) was dissolved in acetonitrile (50 mL) under argon protection and in an ice bath. Tert-butyl nitrite (1.98 g) was added at 0°C and stirred for 30 minutes. Cuprous bromide (4.41 g) was then added. The reaction was heated to 80°C and allowed to react for 2 hours. The reaction was monitored by LCMS. The mixture was filtered, the filtrate was dried, and column chromatography was performed using a 5:1 ratio of petroleum ether to ethyl acetate to afford compound 43-4 (1.58 g).

[0674] Step 5: Synthesis of compound 43-5

[0675] Compound 43-4 (1.58 g) was dissolved in 1,4-dioxane (20 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.14 g), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (540 mg), potassium phosphate (2.35 g), and water (4 mL) were added. The atmosphere was replaced with argon three times, and the mixture was protected by argon. The reaction was heated to 80°C and allowed to react for 3 hours. The reaction was monitored by LCMS. The product was concentrated under reduced pressure and purified by column chromatography using petroleum ether:ethyl acetate = 5:1. Compound 43-5 (670 mg) was obtained.

[0676] Step 6: Synthesis of compound 43-6

[0677] Compound 43-5 (670 mg) was dissolved in methanol (10 mL), and 10% palladium on carbon (217 mg) was added. The atmosphere was replaced with hydrogen three times, and then pressurized with a hydrogen balloon. The reaction was allowed to react at room temperature for 1 hour. The reaction was monitored by LCMS. The system was filtered, and the filtrate was dried to give compound 43-6 (500 mg).

[0678] Step 7: Synthesis of compound 43-7

[0679] Compound 43-6 (500 mg) was dissolved in acetonitrile (10 mL) and saturated with argon. Potassium iodide (2.20 g) and trimethylsilyl chloride (2.16 g) were added at 0°C. The mixture was heated to 80°C and reacted for 1 hour. LCMS monitored the reaction completion. The system was adjusted to a weak base with saturated sodium bicarbonate aqueous solution under an ice bath. 20 mL of water was added to the system, and the mixture was extracted with 100 mL of ethyl acetate. The layers were separated, and the organic phase was washed once with saturated sodium sulfite aqueous solution. The layers were separated, and the organic phase was washed once with saturated sodium chloride aqueous solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography was performed using a 50:1 ratio of dichloromethane to methanol. Compound 43-7 (420 mg) was obtained.

[0680] Step 8: Synthesis of compound 43-8

[0681] Compound 43-7 (420 mg) was dissolved in tetrahydrofuran (10 mL), replaced with argon three times, and then cooled to -30°C. Diisobutylaluminum hydride (1 M, 5.78 mL) was added dropwise. The mixture was allowed to react at -30°C for 2 hours. LCMS monitored the reaction completion. The system was quenched with saturated aqueous ammonium chloride. 50 mL of water was added to the system, and the mixture was extracted with 100 mL of dichloromethane. The layers were separated, and the organic phase was washed once with saturated aqueous sodium chloride. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography was performed using a 50:1 ratio of dichloromethane to methanol to afford compound 43-8 (350 mg).

[0682] Step 9: Synthesis of compound 43-9

[0683] Compound 43-8 (350 mg) was dissolved in acetonitrile (10 mL) and N-bromosuccinimide (225 mg) was added. The reaction was allowed to react at 0°C for 1 hour. LCMS monitored the reaction completion. The system was quenched by adding 1 mL of water, concentrated under reduced pressure, and purified by column chromatography using a 50:1 ratio of dichloromethane to methanol to afford compound 43-9 (320 mg).

[0684] Step 10: Synthesis of compound 43-10

[0685] Compound 43-9 (200 mg) was dissolved in dichloromethane (10 mL), and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (209 mg) and N,N-diisopropylethylamine (202 mg) were added. The reaction was allowed to react at room temperature for 15 hours. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography was performed using a dichloromethane:methanol ratio of 50:1. Compound 43-10 (61 mg) was obtained.

[0686] Step 11: Synthesis of compound 43-11

[0687] Dissolve the raw material N-methylmethylamine hydrochloride (35 mg) in tetrahydrofuran (5 mL), add triethylamine (54 mg), and stir for 30 minutes. Add acetic acid (89 mg), compound 43-10 (33 mg), and sodium cyanoborohydride (33.60 mg). React at room temperature for 2 hours. LCMS monitors the completion of the raw material reaction. Add 20 mL of water to the system, extract with 40 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Column chromatography is performed using dichloromethane:methanol = 50:1. Compound 43-11 (33 mg) is obtained.

[0688] Step 12: Synthesis of compound 43-12

[0689] Compound 43-11 (51 mg) was dissolved in N-methylpyrrolidone (2 mL) and piperazine (135 mg) was added. The reaction was carried out under a nitrogen atmosphere in a microwave oven at 140°C for 45 min. The reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. This yielded compound 43-12 (80 mg, crude product).

[0690] Step 13: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2,5-difluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0691] Compound 43-12 (50 mg) was dissolved in N,N-dimethylformamide (5 mL), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (13 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg), and 1-hydroxybenzotriazole (2 mg) were added. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was separated, and the organic phase was washed once with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by preparative HPLC (column: YMC TA-C18 column, 30 x 150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate; B: acetonitrile. B%: 40% to 70% over 9 min, peak gradient: 65%, RT: 8.5 min, 25 mL / min) and lyophilized to obtain 7 mg of the title compound.

[0692] LC-MS (ESI): m / z = 789.2 [M+H] +

[0693] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.53(s,1H),8.07(d,J=8.5Hz,1H),7.9 6(d,J=2.1Hz,1H),7.87(m,1H),7.70(m,1H),7.61(m,1H),5.35(s,2H),4.52(d ,J=12.4Hz,1H),3.74–3.65(m,2H),3.52(m,4H),3.24(m,1H),3.07–2.98(m,3 H),2.78(m,1H),2.60(m,1H),2.43(s,3H),2.20(s,6H),1.22(t,J=7.5Hz,3H).

[0694] Example 44: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 44)

[0695] Step 1: Synthesis of compound 44-2

[0696] Compound 22-13 (60 mg), raw material 44-1 (58 mg), potassium phosphate (57 mg) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13 mg) were dispersed in water (2 mL) / dioxane (6 mL), protected by nitrogen, and stirred at 90 ° C for 3 hours. Water (20 mL) was added to dilute, extracted with ethyl acetate, separated, and the organic phase was concentrated. Column chromatography (dichloromethane / methanol = 10 / 1) gave compound 44-2 (20 mg).

[0697] Step 2: Synthesis of compound 44-3

[0698] Compound 44-2 (20 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25°C under nitrogen for 2 hours. The reaction was monitored by TLC. Sodium hydroxide solution was added to adjust the pH to approximately 12, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 44-3 (17 mg).

[0699] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro-4-(morpholinomethyl)phenyl)-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0700] Compound 44-3 (17 mg), 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9 mg) and 1-hydroxybenzotriazole (2 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 25°C under nitrogen for 12 hours. After the reaction, the reaction solution was directly prepared (chromatographic column: YMC C18; mobile phase: A is 0.7% NH4HCO3 in H2O; B%: 30% to 60%, B is acetonitrile, 25 mL / min) to obtain 2.1 mg of the title compound.

[0701] LC-MS (ESI): m / z = 824.3 [M+H] +

[0702] 1H NMR(400MHz,Chloroform-d)δ11.90(s,1H),8.62(d,J=6.6Hz,1H),8.51(d,J=9.4Hz,1H),8. 19(d,J=8.5Hz,1H),8.02(d,J=8.5Hz,1H),7.94(d,J=10.0Hz,1H),7.62(s,1H),7.60–7.51(m ,2H),5.67(m,1H),5.33–5.00(m,3H),4.75–4.53(m,2H),3.72(m,4H),3.61(s,2H),3.09–2.9 8(m,1H),2.87–2.68(m,2H),2.57(s,2H),2.51(s,5H),1.36–1.24(m,5H),1.06–1.01(m,1H).

[0703] Example 45: Synthesis of 2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 45)

[0704] Step 1: Synthesis of compound 45-2

[0705] Raw material 45-1 (5.0 g) was dissolved in dichloromethane (50.0 mL), and chloroacetyl chloride (3.6 g) was added dropwise at 0°C. The mixture was then allowed to react at room temperature for 12 h. The reaction was complete. The reaction mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated to give compound 45-2 (5.0 g, crude product).

[0706] Step 2: Synthesis of compound 45-3

[0707] Compound 45-2 (3.0 g) was dissolved in acetonitrile (30.0 mL), and potassium iodide (3.0 g) was added. The mixture was then reacted at 50°C for 2 h. The reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated to give compound 45-3 (3.5 g, crude product).

[0708] Step 3: Synthesis of compound 45-4

[0709] Compound 32-9 (130.0 mg) and compound 45-3 (158.8 mg) were dissolved in dichloromethane (2.0 mL), and N,N-diisopropylethylamine (138.0 mg, 186.0 μL) was added. The mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was concentrated under reduced pressure and the mixture was purified by column chromatography (dichloromethane / methanol gradient elution) to give compound 45-4 (105 mg).

[0710] Step 4: Synthesis of compound 45-5

[0711] Dimethylamine hydrochloride (95.6 mg) was dispersed in methanol (2.0 mL), followed by the addition of triethylamine (148.2 mg). The mixture was stirred at room temperature for 30 minutes, followed by the addition of compound 45-4 (85.0 mg), acetic acid (114.23 mg), and sodium cyanoborohydride (73.6 mg). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to a weak base, and the mixture was extracted with ethyl acetate. The layers were separated, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol gradient elution) to afford compound 45-5 (60.0 mg).

[0712] Step 5: Synthesis of compound 45-6

[0713] Compound 45-5 (50.0 mg) and piperazine (140.8 mg) were added to N-methylpyrrolidone (1.0 mL) under nitrogen atmosphere and reacted at 140°C for 45 min. The reaction was completed. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 45-6 (60.0 mg, crude product).

[0714] Step 6: Synthesis of 2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0715] Compound 45-6 (50.0 mg) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (25.1 mg) were dissolved in N,N-dimethylformamide (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46.7 mg) and 1-hydroxybenzotriazole (1.1 mg) were added and allowed to react at room temperature for 6 h. The reaction was complete. The reaction solution was directly purified by preparative chromatography (column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-60%, B: acetonitrile, 25 mL / min) to obtain 23.0 mg of the title compound.

[0716] LC-MS (ESI): m / z = 751.3 [M+H] + ;

[0717] 1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.43(s,1H),7.99-7.93(m,1H),7.92-7.86(m,1H),7. 73(d,J=8.4Hz,1H),7.65(t,J=8.1Hz,1H),7.60(d,J=2.1Hz,1H),7.55-7.47(m,1H),5.29(s, 2H),4.51(s,1H),3.76-3.68(m,2H),3.64-3.57(m,1H),3.52(s,2H),3.08-3.00(m,4H),2.8 1-2.72(m,1H),2.65-2.57(m,1H),2.40(s,3H),2.36(s,3H),2.20(s,6H),1.27-1.21(m,3H).

[0718] Example 46: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 46)

[0719] Step 1: Synthesis of compound 46-2

[0720] The raw material 46-1 (1.86 g) and compound 38-1 (150 mg) were dissolved in N-methylpyrrolidone (5 mL) and stirred at 140° C. under nitrogen protection for 4 hours. Water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (40 mL*3). The layers were separated, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 46-2 (70 mg).

[0721] Step 2: Synthesis of compound 46-3

[0722] Compound 46-2 (70 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 9, and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 46-3 (40 mg).

[0723] Step 3: Synthesis of compound 46-4

[0724] Compound 46-3 (50 mg), 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (12 mg), 1-hydroxybenzotriazole (5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg) were dissolved in dichloromethane (2 mL) and protected with nitrogen. The mixture was stirred at 25°C for 12 hours, and water (10 mL) was added to dilute the mixture. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 46-4 (50 mg).

[0725] Step 4: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0726] Dimethylamine hydrochloride (43 mg) was dispersed in tetrahydrofuran (4 mL), followed by the addition of triethylamine (64 mg). The mixture was stirred at 25°C for 30 minutes, followed by the addition of acetic acid (47 mg), compound 46-4 (40 mg), and sodium cyanoborohydride (20 mg). The reaction was stirred at 30°C for 1 hour. The pH was adjusted to a weakly alkaline state by the addition of saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phase was concentrated and prepared (chromatographic column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-60%, B: acetonitrile, 25 mL / min) to afford 2.5 mg of the title compound.

[0727] LC-MS (ESI): m / z = 785.2 [M+H] +

[0728] 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.47(s,1H),8.07(d,J=8.6Hz,1H),8.02–7.89(m,3H) ,7.75–7.60(m,2H),5.38(s,2H),4.76(s,1H),4.39(d,J=12.4Hz,1H),3.97–3.89(m,1H),3. 79–3.65(m,2H),3.51(s,2H),3.21–3.11(m,2H),3.04–2.91(m,2H),2.76(d,J=11.5Hz,1H), 2.68–2.54(m,2H),2.42(d,J=5.8Hz,2H),2.18(s,4H),1.46–1.34(m,3H),1.26–1.20(m,3H).

[0729] Example 47: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 47)

[0730] Step 1: Synthesis of compound 47-3

[0731] Compound 47-1 (7.0 g) was dissolved in 6M aqueous hydrochloric acid (21.6 mL). Sodium nitrite (2.5 g) (24.0 mL of water) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 30 min. Urea (215.8 mg) was then added to consume the excess sodium nitrite. The above solution was then added to a solution of compound 47-2 (5.0 g) dissolved in water (180.0 mL) under ice-cooling and allowed to react at room temperature for 1.5 hours. Sodium acetate (10.6 g) in water (180.0 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, solids precipitated at the bottom of the solution. The aqueous phase was decanted and extracted with dichloromethane / methanol (10 / 1) (200.0 mL x 2). The solid was directly dissolved in dichloromethane / methanol (10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield compound 47-3 (8.0 g, crude product).

[0732] Step 2: Synthesis of compound 47-4

[0733] Compound 47-3 (6.0 g) was dissolved in dichloromethane (50.0 mL), and then lead tetraacetate (12.1 g) was slowly added in batches under an ice bath. The reaction was stirred at 50° C. for 2 hours, filtered through silica gel, and the filter cake was washed with dichloromethane / methanol = 10 / 1. The filtrate was concentrated and purified by column chromatography (dichloromethane / methanol gradient elution) to give compound 47-4 (4.5 g).

[0734] Step 3: Synthesis of compound 47-5

[0735] Compound 47-4 (1.0 g) was dispersed in acetonitrile (15.0 mL) and protected by nitrogen. Tert-butyl nitrite (628.2 g) and cuprous bromide (1.8 g) were added under ice bath. Under nitrogen protection, the temperature was raised to 100° C. and stirred for 1 hour. The mixture was filtered through silica gel and the filter cake was washed with dichloromethane / methanol (10 / 1). The filtrate was collected and concentrated under reduced pressure. Compound 47-5 (560.0 mg) was obtained by column chromatography (gradient elution with dichloromethane / methanol).

[0736] Step 4: Synthesis of compound 47-6

[0737] Compound 47-5 (650.0 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (366.1 mg), potassium phosphate (1.0 g) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (232.0 mg) were dispersed in dioxane (8.0 mL) / water (2.0 mL) and stirred at 90°C under nitrogen protection for 2 hours. The reaction mixture was directly concentrated to dryness and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to give compound 47-6 (440.0 mg).

[0738] Step 5: Synthesis of compound 47-7

[0739] Compound 47-6 (700.0 mg) was dispersed in tetrahydrofuran (4.0 mL) / methanol (4.0 mL), and then 10% palladium carbon (70.0 mg) was added. The hydrogen gas was replaced three times and stirred under hydrogen balloon pressure for 2 hours. After the reaction was completed, the mixture was filtered through celite and the filtrate was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain compound 47-7 (700.0 mg, crude product).

[0740] Step 6: Synthesis of compound 47-8

[0741] Compound 47-7 (1.2 g) was weighed and dissolved in acetonitrile (10.0 mL). Trimethylsilyl chloride (5.4 g) and potassium iodide (5.5 g) were added at room temperature and stirred at 80°C for 45 minutes. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to weak alkalinity. The iodine was then quenched with saturated anhydrous sodium sulfite solution. The mixture was allowed to stand and the layers were separated. The acetonitrile phase was concentrated under reduced pressure to a small amount of solvent. The aqueous phase was extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound 47-8 (800.0 mg).

[0742] Step 7: Synthesis of compound 47-9

[0743] Compound 47-8 (800.0 mg) was dissolved in tetrahydrofuran (10.0 mL) under nitrogen protection. Diisobutylaluminum hydride (1M, 144.79 mL) was slowly added dropwise using a constant pressure dropping funnel at -20°C. The reaction was completed when the addition was complete. Saturated ammonium chloride solution was slowly added dropwise at -20°C to quench the reaction. Then, saturated potassium sodium tartrate solution was added at room temperature and stirred at room temperature for 1 hour. After standing, the aqueous phase became clear (with some aqueous and organic phase emulsions). The phases were separated and the emulsion was extracted several times with dichloromethane / methanol = 10 / 1 until all the product was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give compound 47-9 (450 mg).

[0744] Step 8: Synthesis of compound 47-10

[0745] Compound 47-9 (450.0 mg) was dissolved in acetonitrile (10.0 mL), and then NBS (328.4 mg) was added in batches at room temperature. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to dryness and column chromatography (dichloromethane / methanol gradient elution) was performed to obtain compound 47-10 (500.0 mg). Step 9: Synthesis of compound 47-11

[0746] Compound 47-10 (500.0 mg) was dissolved in dichloromethane (10.0 mL), and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (575.9 mg) and N,N-diisopropylethylamine (558.4 mg) were added. The reaction mixture was allowed to react at room temperature for 18 hours. Upon completion of the reaction, the reaction mixture was directly concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to afford compound 47-11 (480.0 mg).

[0747] Step 10: Synthesis of compound 47-12

[0748] Dimethylamine hydrochloride (112.0 mg) was dissolved in methanol (2.0 mL), and triethylamine (173.6 mg) was added. The reaction solution was stirred at room temperature for 20 min. Acetic acid (133.9 mg) and compound 47-11 (100.0 mg) were then added. The reaction solution was stirred at room temperature for 1 h. Sodium cyanoborohydride (86.3 mg) was then added portionwise in an ice bath. The reaction solution was reacted at 25°C for 1 h. The reaction was complete. The reaction solution was extracted with DCM, the organic phase was concentrated, and compound 47-12 (84.0 mg) was obtained by column chromatography (dichloromethane / methanol gradient elution).

[0749] Step 11: Synthesis of compound 47-13

[0750] Compound 47-12 (74.0 mg) was dissolved in N-methylpyrrolidone (1.0 mL), and piperazine (208.4 mg) was added. After addition, the reaction mixture was reacted at 140°C for 45 minutes under nitrogen. The reaction was complete. The reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 47-13 (90.0 mg, crude product).

[0751] Step 12: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)phenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0752] Compound 47-13 (60.0 mg, crude product) was dissolved in N,N-dimethylformamide (1.0 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (30.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55.85 mg), and 1-hydroxybenzotriazole (1.3 mg) were added at room temperature. The reaction solution was reacted at 25°C for 4 hours. The reaction was completed. The reaction solution was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.5% NH4OH in H2O; B%: 60%, B is acetonitrile, 25 mL / min) to obtain 10.0 mg of the title compound.

[0753] LC-MS (ESI): m / z = 753.2 [M+H] +

[0754] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.52(s,1H),8.13-8.02(m,3H),7.97(d,J=2.1H z,1H),7.75-7.65(m,1H),7.59-7.48(m,2H),5.38(s,2H),4.52(d,J=12.1Hz,1H),3.77 -3.66(m,2H),3.48-3.44(m,3H),3.24-3.21(m,1H),3.07-3.00(m,2H),2.98-2.92(m,1 H),2.80-2.73(m,1H),2.62-2.57(m,1H),2.43(s,3H),2.17(s,6H),1.24-1.19(m,3H).

[0755] Example 48: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 48)

[0756] Step 1: Synthesis of compound 48-2

[0757] Compound 47-11 (150.0 mg) and p-toluenesulfonic acid (8.9 mg) were dissolved in toluene (3.0 mL), and ethylene glycol (63.9 mg) was added. The mixture was stirred at 100°C under nitrogen for 2 hours, and the reaction was completed. The solvent was directly concentrated under reduced pressure, and the mixture was purified by column chromatography (dichloromethane / methanol gradient elution) to give compound 48-2 (130.0 mg).

[0758] Step 2: Synthesis of compound 48-3

[0759] Piperazine (322.6 mg) and compound 48-2 (120.0 mg) were dissolved in N-methylpyrrolidone (0.2 mL) and stirred in a microwave at 140° C. for 1 hour under nitrogen protection. After the reaction was completed, water (10.0 mL) was added for dilution, and the mixture was extracted with ethyl acetate three times. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 48-3 (120.0 mg, crude product).

[0760] Step 3: Synthesis of compound 48-4

[0761] Compound 48-3 (100.0 mg), 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (48.7 mg), 1-hydroxybenzotriazole (2.1 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90.7 mg) were dissolved in N,N-dimethylformamide (2.0 mL), stirred and reacted at 25°C for 12 hours, diluted with water (20.0 mL), extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 48-4 (60.0 mg).

[0762] Step 4: Synthesis of compound 48-5

[0763] Compound 48-4 (60.0 mg) was dissolved in hydrochloric acid (0.6 mL, 2 M) and tetrahydrofuran (0.6 mL) and stirred at 55°C for 1 h. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH to near neutral, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 48-5 (50.0 mg).

[0764] Step 5: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0765] 3-Fluoroazetidine hydrochloride (61.6 mg) was dissolved in methanol (1.0 mL), followed by the addition of triethylamine (69.7 mg). The mixture was stirred at room temperature for 20 minutes, followed by the addition of 48-5 (50.0 mg), acetic acid (53.8 mg), and sodium cyanoborohydride (34.7 mg). The reaction was allowed to react at room temperature for 1 hour. The reaction was complete. The mixture was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried and concentrated to prepare the mixture (chromatographic column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30% to 70%, B: acetonitrile, 25 mL / min) to obtain 10.0 mg of the title compound.

[0766] LC-MS (ESI): m / z = 783.2 [M+H] +

[0767] 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.50(s,1H),8.12-8.04(m,3H),7.97(d,J=2.1Hz,1H),7 .72-7.67(m,1H),7.55-7.48(m,2H),5.38(s,2H),5.28(m,1H),5.09(m,1H),4.51(d,J=12.3Hz, 1H),3.77-3.66(m,4H),3.62-3.51(m,3H),3.21-3.17(m,1H),3.16-3.12(m,1H),3.07-3.00(m ,2H),2.99-2.92(m,1H),2.80-2.74(m,1H),2.61-2.56(m,1H),2.42(s,3H),1.24-1.19(m,3H).

[0768] Example 49: Synthesis of 2-(2-(4-((3-azabicyclo[3.1.0]hex-3-yl)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 49)

[0769] The raw material 3-azabicyclo[3.1.0]hexane hydrochloride (26 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine (28 mg, 37.59 μL) was added. The mixture was stirred at room temperature for 30 minutes. Acetic acid (25 mg) and compound 38-4 (20 mg) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (14 mg) was added. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The organic phase was separated and washed once with saturated sodium chloride aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by reverse-phase high-performance liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate solution; B: acetonitrile. B%: 55%-85% in 9.2 min, gradient: 75%, RT: 8.5 min, 25 mL / min) and lyophilized to obtain 7 mg of the title compound.

[0770] LC-MS (ESI): m / z = 809.2 [M+H] +

[0771] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.52(s,1H),8.07(d,J=8.5Hz,1H),8.00–7.93(m,2H),7.90( m,1H),7.70(m,1H),7.60(t,J=8.1Hz,1H),5.38(s,2H),4.52(d,J=12.3Hz,1H),3.70(m,3H),3.50( m,2H),3.27–3.18(m,2H),3.07–2.92(m,3H),2.89(d,J=8.5Hz,2H),2.77(m,1H),2.60(m,1H),2.43 (s,3H),2.37(d,J=8.3Hz,2H),1.39–1.33(m,2H),1.22(t,J=7.4Hz,3H),0.65(m,1H),0.32(m,1H).

[0772] Example 50: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-6-(3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-azabicyclo[4.1.0]hept-6-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 50)

[0773] Step 1: Synthesis of compound 50-1

[0774] 3-Fluoroazetidine hydrochloride (183.8 mg) was dissolved in methanol (2.0 mL), and triethylamine (208.4 mg, 2.1 mmol) was added. The mixture was stirred at room temperature for 10 min, and then compound 47-11 (120.0 mg), acetic acid (160.6 mg) and sodium cyanoborohydride (103.5 mg) were added in sequence, and then reacted at room temperature for 1 h. The reaction was completed. Saturated sodium bicarbonate solution was added to the reaction solution, and then extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 50-1 (100.0 mg).

[0775] Step 2: Synthesis of compound 50-3

[0776] Compound 50-2 (99.2 mg, 327.4 μmol) and compound 50-1 (120.0 mg) were dissolved in water (0.2 mL) and toluene (1.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (29.5 mg) and cesium carbonate (106.6 mg) were added. The mixture was then reacted in a microwave oven at 110°C under nitrogen for 50 min. The reaction was complete. The reaction solution was directly concentrated to dryness and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain compound 50-3 (25.0 mg).

[0777] Step 3: Synthesis of compound 50-4

[0778] Compound 50-3 (25.0 mg) was dissolved in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) and allowed to react at room temperature for 30 min. The reaction mixture was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 50-4 (30.0 mg, crude product).

[0779] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-6-(3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-azabicyclo[4.1.0]hept-6-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0780] Compound 50-4 (20.0 mg) and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (6.6 mg) were dissolved in N,N-dimethylformamide (0.4 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.5 mg) and 1-hydroxybenzotriazole (410.6 μg) were added and allowed to react at room temperature for 6 h. Upon completion of the reaction, the reaction solution (chromatographic column: YMC TA column; mobile phase: A: 7 mmol NH4HCO3 aqueous solution; B: acetonitrile, B%: 40% to 70%, 40 mL / min) yielded 2.0 mg of the title compound.

[0781] LC-MS (ESI): m / z = 794.2 [M+H] +

[0782] 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.12-8.01(m,3H),7.96(s,1H),7.69(d ,J=8.6Hz,1H),7.55-7.48(m,2H),5.39-5.29(m,2H),5.28-5.10(m,1H),4.04 -3.95(m,1H),3.93-3.80(m,2H),3.79-3.75(m,1H),3.72-3.68(m,2H),3.66-3.63(m,1H),3. 62-3.51(m,4H),3.23-3.11(m,4H),3.02-2.92(m,2H),2.79-2.71(m,3H),1.30-1.22(m,3H).

[0783] Example 51: Synthesis of 2-(2-(4-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 51)

[0784] Compound 51-1 (48 mg) was dispersed in tetrahydrofuran (5 mL), followed by the addition of triethylamine (95 mg). The mixture was stirred at 25°C for 30 minutes, followed by the addition of compound 38-4 (100 mg), sodium triacetoxyborohydride (85 mg), and acetic acid (80 mg). The reaction was stirred at 25°C for 2 hours. The pH was adjusted to a weakly alkaline state by the addition of saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phase was concentrated and prepared (chromatographic column: YMC C18; mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 30%-60%, B: acetonitrile, 25 mL / min) to afford 10 mg of the title compound.

[0785] LC-MS (ESI): m / z = 809.2 [M+H] +

[0786] 1H NMR (400MHz, CDCl3) δ8.58(s,1H),8.51(d,J=8.7Hz,1H),8.34(m,1H),8.00(d,J=8 .2Hz,1H),7.93–7.84(m,1H),7.73(m,1H),7.61(s,1H),7.54(m,1H),5.59(m,1H), 5.17(s,2H),4.80(m,1H),4.01(m,3H),3.86(s,2H),3.49(m,2H),3.15(m,3H),2.8 4–2.72(m,4H),2.57(s,3H),1.76(s,2H),1.62–1.52(m,2H),1.34(t,J=7.5Hz,3H).

[0787] Example 52: Synthesis of 2-(2-(4-((2-azabicyclo[3.1.0]hex-2-yl)methyl)-3-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 52)

[0788] 2-Azabicyclo[3.1.0]hexane hydrochloride (48 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine (94.95 mg) was added, and the reaction solution was stirred at room temperature for 1 h. Acetic acid (80.8 mg) and compound 38-4 (100 mg) were added, and the reaction solution was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (114 mg) was added in batches under ice bath. After the addition was complete, the reaction solution was reacted at 25 ° C for 1 hour. The reaction was monitored by LCMS. The reaction solution was extracted with DCM, the organic phase was concentrated, and the product was prepared (chromatographic column: YMC C 18 ; Mobile phase: A is 0.5% NH4OH in H2O; B%: 60%, B is acetonitrile, 25 mL / min) to obtain 20 mg of the title compound.

[0789] LC-MS (ESI): m / z = 809.2 [M+H] +

[0790] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.58(s,1H),8.07(d,J=8.5Hz,1H),7.98(m,2H) ,7.92(m,1H),7.72(m,2H),5.39(s,2H),4.52(d,J=12.3Hz,1H),3.70(m,4H),3.50(d, J=12.5Hz,1H),3.22(m,1H),3.07-2.94(m,3H),2.80(m,2H),2.60(m,2H),2.45(s,3H) ,1.98(m,1H),1.83(m,2H),1.42-1.33(m,1H),1.21(m,3H),0.71(m,1H),0.08(m,1H).

[0791] Example 53: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 53)

[0792] Step 1: Synthesis of compound 53-1

[0793] Intermediate 29-7 (158 mg) and (S)-3-fluoropyrrolidine (297.74 mg, HC) were dissolved in acetonitrile (6 mL). Potassium carbonate (393.23 mg) was added to the mixture and allowed to react at room temperature for 3 h. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 53-1 (144.8 mg).

[0794] Step 2: Synthesis of compound 53-2

[0795] Compound 53-1 (144.8 mg) was dissolved in acetonitrile (15 mL). A solution of N-bromosuccinimide (79.27 mg) in acetonitrile (2 mL) was then added dropwise at 0°C. The resulting mixture was reacted at room temperature for 1 h. After completion of the reaction, the reaction solution was extracted with DCM, and the organic phase was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[0796] Step 3: Synthesis of compound 53-3

[0797] Compound 53-2 (178.3 mg) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (161.92 mg) were dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (109.66 mg, 147.79 μL) was added to the solution, and the resulting mixture was allowed to react at room temperature for 40 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:10) to obtain compound 53-3 (185.5 mg).

[0798] Step 4: Synthesis of compound 53-4

[0799] Compound 53-3 (185.5 mg) and piperazine (487.23 mg) were dissolved in N-methylpyrrolidone (4 mL), and the resulting mixture was placed under microwave at 140 ° C for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate, the reaction solution was washed with water, and the organic phase was concentrated under reduced pressure to obtain a crude product that was directly used in the next reaction. Step 5: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0800] Compound 53-4 (186.98 mg), 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (65.39 mg), 1-hydroxybenzotriazole (11.47 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (162.66 mg) were dissolved in N,N-dimethylformamide (2 mL), and the resulting mixture was reacted at room temperature for 2 h. After completion of the reaction, the mixture was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L aqueous NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio: 30-60%, elution time: 10 min) to obtain 47 mg of the title compound.

[0801] LC-MS (ESI): m / z = 797.2 [M+H] +

[0802] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.49(s,1H),8.08(m,3H),7.96(d,J=2.1Hz,1H),7.70(m,1H),7.5 8–7.53(m,2H),5.38(s,2H),5.30–5.25(m,1H),5.13(m,1H),4.52(d,J=12.5Hz,1H),3.73(m,1H),3.69( m,2H),3.51(d,J=12.5Hz,1H),3.03(m,2H),2.96(m,1H),2.85–2.75(m,2H),2.71–2.64(m,1H),2.62–2. 58(m,1H),2.42(s,3H),2.39–2.30(m,2H),2.26–2.07(m,2H),2.03–1.80(m,2H),1.22(t,J=7.4Hz,3H).

[0803] Example 54: Synthesis of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 54)

[0804] Using (R)-3-fluoropyrrolidine as the starting material, 8.5 mg of the title compound was obtained by referring to the synthesis method of Example 53.

[0805] LC-MS (ESI): m / z = 797.2 [M+H] +

[0806] 1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.49(s,1H),8.08(m,3H),7.96(s,1H),7.70(m,1H) ,7.56(d,J=8.4Hz,2H),5.38(s,2H),5.28(m,1H),4.51(m,1H),3.72(s,1H),3.69(s,2H), 3.03(d,J=7.8Hz,2H),2.95(m,1H),2.85–2.73(m,3H),2.71–2.65(m,1H),2.60(m,1H),2. 42(s,3H),2.36(d,J=7.2Hz,2H),2.25–2.08(m,2H),2.02–1.81(m,2H),1.24–1.19(m,3H).

[0807] Example 55: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 55)

[0808] Step 1: Synthesis of compound 55-2

[0809] The raw material 4-amino-3-fluoro-N-methoxy-N-methyl-benzamide 55-1 (7.05 g) was dissolved in water (50 mL). Hydrochloric acid (6 M, 21.33 mL) and sodium nitrite (2.45 g) were added at 0°C and stirred for 30 minutes. Urea (214 mg) was added and stirred for 10 minutes. 4-Methoxypyridine-2,6-diamine (9 g) was added and the mixture was allowed to warm to room temperature for 2 hours. Sodium acetate (10.49 g mg) was added. The reaction was allowed to proceed at room temperature for 5 hours, and the reaction was monitored by LCMS. The pH was adjusted to alkaline with 5N aqueous sodium hydroxide solution. The solid was filtered and the filter cake was collected. The filtrate was extracted with 200 mL of dichloromethane, the layers were separated, and the organic phase was washed with saturated aqueous sodium chloride solution. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 55-2 (12.10 g, crude).

[0810] Step 2: Synthesis of compound 55-3

[0811] Dissolve raw material 55-2 (11.6 g) in dichloromethane (200 mL) and add lead tetraacetate (14.75 g). Heat to 50°C and react for 3 hours. Completion of the reaction is monitored by LCMS. Filter the system, spin-dry the filtrate, and perform column chromatography using a 50:1 ratio of dichloromethane to methanol to obtain compound 55-3 (10.42 g, crude).

[0812] Step 3: Synthesis of compound 55-4

[0813] Compound 55-3 (9.92 g) was dissolved in acetonitrile (200 mL) under argon. Tert-butyl nitrite (7.38 g) and ketone bromide (16.44 g) were added at 0°C. The mixture was heated to 100°C for 3 hours. The reaction was monitored by LCMS. The mixture was filtered, the filtrate was concentrated to dryness, and column chromatography using dichloromethane:methanol = 50:1 was performed to obtain compound 55-4 (4.01 g).

[0814] Step 4: Synthesis of compound 55-5

[0815] Compound 55-4 (3.9 g) was dissolved in 1,4-dioxane (40 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.93 g), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.39 g), potassium phosphate (6.05 g), and water (8 mL) were added. The atmosphere was replaced with argon three times, and the mixture was protected by argon. The reaction was heated to 80°C and allowed to react for 3 hours. The reaction was monitored by LCMS. 30 mL of water was added to the system, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was separated and washed with saturated sodium chloride aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography using dichloromethane:methanol = 80:1 was performed to obtain compound 55-5 (3.0 g).

[0816] Step 5: Synthesis of compound 55-6

[0817] Compound 55-5 (3.0 g) was dissolved in methanol (50 mL), and Pd / C (500 mg, 10%) was added. The atmosphere was replaced with hydrogen three times and pressurized with a hydrogen balloon. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LCMS. The system was filtered, and the filtrate was dried to give compound 55-6 (2.85 g).

[0818] Step 6: Synthesis of compound 55-7

[0819] Compound 55-6 (2.75 g) was dissolved in acetonitrile (30 mL), and potassium iodide (12.70 g) and trimethylsilyl chloride (12.40 g) were added. The mixture was heated to 80°C and reacted for 2 hours. The pH of the system was adjusted to neutral with a saturated aqueous sodium bicarbonate solution under an ice bath. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed with a saturated aqueous sodium bisulfite solution. The organic phase was separated, and the organic phase was washed with a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 55-7 (1.20 g).

[0820] Step 7: Synthesis of compound 55-8

[0821] Compound 55-7 (1.20 g) was dissolved in tetrahydrofuran (20 mL) under argon protection, cooled to -30°C, and diisobutylaluminum hydride (1 M, 17.37 mL) was added dropwise. The reaction was allowed to react for 2 hours, and the reaction was completed after LCMS monitoring. The system was quenched with saturated aqueous ammonium chloride solution, 40 mL of water was added to the system, and the system was extracted with 150 mL of dichloromethane. The layers were separated, and the organic phase was washed with saturated aqueous sodium chloride solution. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 55-8 (990 mg).

[0822] Step 8: Synthesis of compound 55-9

[0823] Compound 55-8 (990 mg) was dissolved in acetonitrile (10 mL) and N-bromosuccinimide (677 mg) was added at 0°C. The reaction was allowed to proceed at 0°C for 2 hours. Completion of the reaction was monitored by LCMS. 20 mL of water was added to the system, and a solid precipitated. This solid was filtered and purified by column chromatography (dichloromethane:methanol = 50:1) to afford compound 55-9 (1.11 g).

[0824] Step 9: Synthesis of compound 55-10

[0825] Compound 55-9 (1.11 g) was dissolved in dichloromethane (15 mL), and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (1.44 g) and N,N-diisopropylethylamine (1.18 g, 1.59 mL) were added. The reaction was allowed to proceed at 40°C for 15 hours. LCMS monitored the reaction completion. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography (dichloromethane:methanol = 50:1) afforded compound 55-10 (700 mg).

[0826] Step 10: Synthesis of compound 55-11

[0827] Compound 55-10 (300 mg) was dissolved in tetrahydrofuran (10 mL), and dimethylamine tetrahydrofuran solution (2M, 1.25 mL) and acetic acid (209 mg) were added. The mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (318 mg) was added. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography (dichloromethane:methanol = 30:1) gave compound 55-11 (300 mg).

[0828] Step 11: Synthesis of compound 55-12

[0829] Compound 55-11 (280 mg) was dissolved in N-methylpyrrolidone (18 mL) and piperazine (766 mg) was added. The reaction was microwaved at 140°C for 45 minutes. LCMS monitored the reaction completion. 40 mL of water was added to the system, and the mixture was extracted with 80 mL of ethyl acetate. The layers were separated, and the organic phase was washed with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product 55-12 (280 mg) was obtained.

[0830] Step 12: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-((dimethylamino)methyl)-2-fluorophenyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0831] Compound 55-12 (280 mg) was dissolved in N,N-dimethylformamide (5 mL), and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (75 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mg), and 1-hydroxybenzotriazole (12 mg) were added. The reaction was allowed to react at room temperature for 2 hours, and the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was separated, and the organic phase was washed once with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound (19 mg) was obtained by reverse-phase high performance liquid chromatography (chromatographic column: YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase: A: 7 mmol / L aqueous ammonium bicarbonate solution; B: acetonitrile. B%: 25%-60% in 10.5 min, elution gradient: 65%, RT: 8.5 min. 25 mL / min) and lyophilization.

[0832] LC-MS (ESI): m / z = 771.2 [M+H] +

[0833] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.55(s,1H),8.07(d,J=8.6Hz,1H),7.96(s, 1H),7.87(t,J=8.0Hz,1H),7.70(m,1H),7.48(m,1H),7.38(m,1H),5.35(s,2H),4.5 2(d,J=12.5Hz,1H),3.71(m,2H),3.50(s,2H),3.47(m,1H),3.23(m,1H),3.07–2.94 (m,3H),2.78(m,1H),2.60(m,1H),2.44(s,3H),2.19(s,6H),1.21(t,J=7.5Hz,3H).

[0834] Example 56: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(6-((3-fluoroazetidinyl)methyl)pyridin-3-yl)-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 (Compound 56)

[0835] Compound 56-1 (200 mg) was dissolved in a mixture of dioxane (5 mL) and water (1 mL). A solution of Int-1 (72.12 mg) in dioxane (2 mL), tetrakistriphenylphosphine palladium (49.62 mg), and potassium carbonate (158.20 mg) were added at room temperature. After the addition was complete, the reaction mixture was reacted at 80°C for 10 hours under nitrogen protection. The reaction was monitored by LCMS. The reaction mixture was concentrated and purified by column chromatography (methanol / dichloromethane = 0-10%) to obtain a crude product, which was then purified by preparative chromatography (chromatographic column: YMC C 18 ; Mobile phase: A: 0.7% NH4HCO3 in H2O; B%: 50%, B: acetonitrile, 25 mL / min) to obtain 60 mg of the title compound. LC-MS (ESI): m / z = 784.2 [M+H] +

[0836] 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.16(d,J=2.1Hz,1H),8.46(s,1H),8.39(dd,J=8.2,2.2Hz,1H),8. 05(d,J=8.6Hz,1H),7.96(d,J=2.0Hz,1H),7.71(dd,J=8.8,2.1Hz,1H),7.52(d,J=8.2Hz,1H),5.41(s,2H ),5.21(m,1H),4.54(d,J=12.4Hz,1H),3.82(s,2H),3.69–3.61(m,2H),3.56–3.47(m,3H),3.32–3.26(m, 2H),3.26–3.21(m,1H),3.06–2.96(m,3H),2.84(m,1H),2.67(m,1H),2.42(s,3H),1.22(t,J=7.3Hz,3H).

[0837] Synthesis of 56-1

[0838] Step 1. Synthesis of compound 56-2

[0839] 5-Bromo-2-(chloromethyl)pyridine (200 mg, 968.68 μmol) and 3-fluoroazetidine hydrochloride (330.85 mg, 2.97 mmol) were dispersed in acetonitrile (5 mL). Potassium carbonate (802.06 mg, 5.81 mmol) was added and the mixture was heated to 70°C and stirred for 2 hours until the reaction was complete. The mixture was filtered, the filtrate was concentrated, and column chromatography (ethyl acetate / petroleum ether = 0-50%) was performed to obtain 56-2 (220 mg, 93% yield) as a yellow oil.

[0840] LC-MS(ESI):m / z=245.0 / 247.0[M+H] + ;

[0841] Step 2: Synthesis of Compound 56-1

[0842] 56-2 (90 mg, 367.21 umol) and diboronic acid pinacol ester (186.50 mg, 734.42 umol) were dissolved in dioxane (5 mL), and potassium acetate (107.96 mg, 1.10 mmol) and tetrakistriphenylphosphine palladium (63.67 mg, 55.08 umol) were added at room temperature. After the addition was completed, the reaction solution was reacted at 110 ° C for 6 hours under nitrogen protection, cooled to room temperature, filtered, and used directly in the next step.

[0843] LC-MS (ESI): m / z = 211.1 [M+H] + ;

[0844] Example 57: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-((1s,3s)-3-fluorocyclobutyl)-1,2,3,6-tetrahydropyridin-4-yl)-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 (Compound 57)

[0845] Step 1: Synthesis of compound 57-1

[0846] Dissolve N,N-diisopropylethylamine (100 mg, 776.95 μmol, 135.33 μL) in dichloromethane (5 mL) under argon. Cool to -78°C and add trifluoromethanesulfonic anhydride (172 mg, 610.46 μmol, 102.70 μL) dropwise. Stir for 10 minutes, then add trans-3-fluorocyclobutanol (50 mg, 554.96 μmol). Warm to room temperature and react for 15 hours. After the reaction, proceed directly to the next step.

[0847] Step 2: Synthesis of compound 57-2

[0848] To a solution of compound 57-1 (123 mg, 553.66 μmol) in DCM (5 mL) was added N,N-diisopropylethylamine (286 mg, 2.21 mmol, 385.74 μL), followed by the addition of 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (116 mg, 553.66 μmol) at 0°C. The mixture was allowed to warm to room temperature and allowed to react for 15 hours. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude title compound (155 mg) was obtained and used directly in the next step.

[0849] Step 3: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-((1s,3s)-3-fluorocyclobutyl)-1,2,3,6-tetrahydropyridin-4-yl)-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

[0850] Intermediate Int-1 (149 mg, 213.39 μmol) was dissolved in 1,4-dioxane (10 mL), and compound 57-2 (150 mg, 533.48 μmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (31 mg, 42.68 μmol), potassium phosphate (136 mg, 640.18 μmol), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the mixture was protected by argon. The reaction was heated to 70°C and allowed to react for 6 hours. The reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was separated and washed once with saturated sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was separated by reverse-phase high performance liquid chromatography (chromatographic column: YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase: A is 7 mmol / L ammonium bicarbonate aqueous solution; B is acetonitrile. B%: 45%-75% in 8 min, peak gradient: 65%, RT: 8.5 min. 25 mL / min) and lyophilized to obtain 33 mg of the title compound.

[0851] LC-MS (ESI): m / z = 773.3 [M+H] +

[0852] 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.44(s,1H),8.05(d,J=8.5Hz,1H),7 .96(s,1H),7.71(m,1H),6.78(m,1H),5.31(s,2H),4.86(m,1H),4.51(d,J= 12.3Hz,1H),3.53–3.45(m,5H),3.27–3.18(m,3H),2.98(m,5H),2.80(m,1H ),2.64–2.53(m,3H),2.41(s,4H),2.05–1.88(m,2H),1.18(t,J=7.4Hz,3H).

[0853] Example 58: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-((1r,3r)-3-fluorocyclobutyl)-1,2,3,6-tetrahydropyridin-4-yl)-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 (Compound 58)

[0854] Using raw material cis-3-fluorocyclobutanol 38 mg of the title compound was obtained by referring to the synthesis method of Example 57.

[0855] LC-MS (ESI): m / z = 773.3 [M+H] +

[0856] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.05(d,J=8.5Hz,1H),7.95(s,1H),7 .70(d,J=8.8Hz,1H),6.78(m,1H),5.30(s,2H),5.25–5.06(m,1H),4.50(d ,J=12.3Hz,1H),3.45(m,5H),3.25–3.18(m,2H),3.08–2.90(m,6H),2.78( m,1H),2.57(m,3H),2.37(s,3H),2.34–2.18(m,4H),1.17(t,J=7.4Hz,3H).

[0857] Example 59: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (Compound 59)

[0858] Step 1: Synthesis of compound 59-1

[0859] Dissolve methyl 3-oxopentanoate (35.0 g, 268.9 mmol, 33.7 mL) in dichloromethane (300 mL) under argon protection and in an ice bath. Add sulfonyl chloride (47.2 g, 349.6 mmol) dropwise. After addition, warm to room temperature and react for 15 hours. Monitor the reaction by TLC. Remove the solvent under reduced pressure, add 300 mL of dichloromethane to the system, extract, wash once with saturated sodium chloride solution, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain a crude product (48 g).

[0860] Step 2: Synthesis of compound 59-2

[0861] Dissolve raw material 59-1 (48.0 g, 291.6 mmol) in acetonitrile (300 mL), add triethylamine (88.5 g, 874.9 mmol, 121.9 mL), cool in an ice bath, and add N-tert-butyloxycarbonylpiperazine (54.3 g, 291.6 mmol) dropwise. Heat to 60°C and react for 15 hours. Completion of the reaction is monitored by LCMS. Cool the system, filter, and concentrate the filtrate. Dissolve the system in dichloromethane, wash the system once with saturated aqueous citric acid, separate the layers, and wash the organic phase once with saturated aqueous sodium chloride. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Column chromatography using petroleum ether:ethyl acetate in a ratio of 5:1 yields the title compound (40 g).

[0862] Step 3: Synthesis of compound 59-3

[0863] Dissolve the raw material 4-nitro-2H-1,2,3-triazole (25.0 g, 219.2 mmol) in N,N-dimethylformamide (300 mL), add 4-methoxybenzyl chloride (51.5 g, 328.8 mmol) and potassium carbonate (45.4 g, 328.8 mmol). Reaction is allowed to proceed at 60°C for 6 hours. After completion of the reaction, monitor the reaction by LCMS. Pour the mixture into 100 mL of ice water and stir with 50 mL of a 5:1 ratio of petroleum ether to ethyl acetate. Filter the mixture and rinse the filter cake with a 5:1 ratio of petroleum ether to ethyl acetate. Dry the filter cake to obtain the title compound (24.6 g).

[0864] Step 4: Synthesis of compound 59-4

[0865] Dissolve raw material 59-3 (24.6 g, 105.0 mmol) in methanol (200 mL), add a solution of ammonium chloride (28.4 g, 530.9 mmol) in water (50 mL), stir, and add iron powder (17.6 g, 315.1 mmol). Heat the reaction to 70°C for 10 hours. LCMS monitors the reaction completion. Filter the mixture while hot, concentrate the filtrate, add 80 mL of water, extract with 200 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain the product (16.2 g).

[0866] Step 5: Synthesis of compound 59-5

[0867] Dissolve raw material 59-4 (8.6 g, 41.9 mmol) in ethanol (50 mL), add raw material 59-2 (14.5 g, 46.1 mmol) and p-toluenesulfonic acid (722.0 mg, 4.2 mmol). React at 100°C for 15 hours. LCMS monitors the reaction completion. Remove the solvent under reduced pressure, then add 50 mL of water to the system. Extract with 100 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Column chromatography using petroleum ether:ethyl acetate in a ratio of 5:1 yields the title compound (13.6 g).

[0868] Step 6: Synthesis of compound 59-6

[0869] Raw material 59-5 (11.0 g, 21.9 mmol) was dissolved in diphenyl ether (12 mL) in batches. The reaction was microwaved at 220°C for 20 minutes. The mixture was poured into petroleum ether and stirred. A solid precipitated and was filtered. The filter cake was dissolved in dichloromethane and concentrated. Dichloromethane and di-tert-butyl dicarbonate (7.2 g, 32.9 mmol) were added to the mixture and allowed to react at room temperature for 3 hours. The reaction was monitored by LCMS. The mixture was concentrated and purified by column chromatography using a 50:1 ratio of dichloromethane to methanol to afford the title compound (590 mg).

[0870] Step 7: Synthesis of compound 59-7

[0871] Dissolve raw material 59-6 (800 mg, 1.7 mmol) in N,N-dimethylformamide (5 mL), add tert-butyl bromoacetate (666.0 mg, 3.4 mmol, 500.8 μL) and N,N-diisopropylethylamine (662 mg, 5.1 mmol, 892.2 μL). React at 80°C for 3 hours. Completion of the reaction was monitored by LCMS. Add 20 mL of water to the system, extract with 40 mL of ethyl acetate, separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Column chromatography using petroleum ether:ethyl acetate in a ratio of 5:1 yields the title compound (300 mg).

[0872] Step 8: Synthesis of compound 59-8

[0873] Dissolve raw material 59-7 (300 mg, 514.8 μmol) in ethanol (3 mL), add 10% palladium on carbon (100 mg) and 20% palladium hydroxide on carbon (100 mg). Replace the atmosphere with hydrogen three times, pressurize with a hydrogen balloon, heat to 78°C, and react for 20 hours. Cool the mixture, filter, and concentrate the filtrate. Slurry the mixture with petroleum ether:ethyl acetate = 5:1, and filter to obtain the title compound (120 mg).

[0874] Step 9: Synthesis of compound 59-9

[0875] Starting material 59-8 (120 mg, 259.4 μmol) was dissolved in dichloromethane (5 mL), and 2-methoxypyridine-4-boronic acid (79 mg, 516.5 μmol), copper acetate (141 mg, 706.3 μmol), and pyridine (204.9 mg, 2.6 mmol) were added. The mixture was purged with oxygen three times, protected with oxygen, and allowed to react at room temperature for 3 days. LCMS monitored the reaction for complete reaction. The mixture was filtered through celite, and the filtrate was added with 20 mL of water and extracted with 40 mL of dichloromethane. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography using a dichloromethane:methanol ratio of 80:1 was performed to obtain the title compound (109 mg).

[0876] Step 10: Synthesis of compound 59-10

[0877] Dissolve starting material 59-9 (109 mg, 191.4 μmol) in methanol (5 mL) and add aqueous sodium hydroxide (1 M, 382.7 μL). Allow to react at room temperature for 15 hours, monitoring the reaction completion by LCMS. Part of the solvent was removed by rotary evaporation, and the system was dissolved in 20 mL of dichloromethane. Add 20 mL of water, adjust the pH to 2 with 2N dilute hydrochloric acid, and extract with 20 mL of dichloromethane. Separate the layers, and wash the organic phase once with saturated sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain the title compound (106 mg, crude product).

[0878] Step 11: Synthesis of compound 59-11

[0879] Starting material 59-10 (90 mg, 175.2 μmol) was dissolved in acetonitrile (4 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (147 mg, 525.8 μmol) and 2,4,6-trimethylpyridine (106 mg, 876.3 μmol, 115.9 μL) were added at room temperature. Stir at room temperature for 5 minutes. 3-Chloro-4-aminobenzotrifluoride (52 mg, 262.9 μmol, 35.8 μL) was added. The temperature was raised to 60°C and the reaction was allowed to react for 2 hours. Completion of the reaction was monitored by LCMS. 20 mL of water was added to the system, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was separated and washed once with saturated sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography using dichloromethane:methanol = 80:1 was performed to obtain the title compound (100 mg).

[0880] Step 12: Synthesis of compound 59-12

[0881] Dissolve starting material 59-11 (100 mg, 144.7 μmol) in dichloromethane (3 mL) and add trifluoroacetic acid (83 mg, 727.9 μmol, 55.7 μL). Allow to react at room temperature for 1 hour. LCMS monitors the reaction completion. Add 10 mL of water and 10 mL of dichloromethane to the system, adjust the pH to 14 with 2N aqueous sodium hydroxide solution, extract with 40 mL of dichloromethane, separate the layers, and wash the organic phase once with saturated aqueous sodium chloride solution. Separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain the title compound (60 mg).

[0882] Step 13: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0883] Starting material 59-12 (60 mg, 101.5 μmol) was dissolved in dichloromethane (3 mL), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (26.6 mg, 172.6 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.0 mg, 203.1 μmol), and 1-hydroxybenzotriazole (3.4 mg, 25.4 μmol) were added. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LCMS. Under weak acidity, 20 mL of water was added to the system, and the mixture was extracted with 40 mL of dichloromethane. The organic phase was separated, washed once with saturated sodium chloride aqueous solution, separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was sent for preparation and purified by reverse-phase high performance liquid chromatography (chromatographic column: YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase: A is 0.5‰ formic acid aqueous solution; B is acetonitrile. B%: 58%-70%, 25 mL / min). The target product peak was collected and lyophilized to obtain compound 59 (10 mg).

[0884] LC-MS (ESI): m / z = 727.2 [M+H] +

[0885] 1H NMR (400MHz, Chloroform-d) δ11.82(s,1H),8.58(s,1H),8.51(d,J=8.7Hz,1H),8.29(d,J=5.7Hz,1H),8.24(s,1H),7.71(m,1H),7.63(m,1H),7.57–7. 52(m,2H),5.63(m,1H),5.16(s,2H),4.78(m,1H),4.00(m,5H),3.49(m,1H) ,3.15(m,1H),3.06(m,1H),2.81(m,3H),2.56(s,3H),1.35(d,J=7.4Hz,3H).

[0886] Biological activity and related properties test examples

[0887] The compounds in the following test examples were all prepared according to the methods of the above embodiments of the present disclosure.

[0888] Test Example 1: WRN ATP hydrolase inhibitory activity assay

[0889] Experimental Principle

[0890] WRN unwinding is driven by ATP hydrolysis by the ATP hydrolase domain of the WRN protein. ATP hydrolysis generates ADP, which releases energy to promote WRN unwinding. The ADP generated during the reaction is detected using the ADP-Glo ​​assay kit (Promega). The signal value after adding the assay reagent is positively correlated with the amount of ADP generated in the reaction system, and changes in the signal value reflect changes in the ATP hydrolase activity of the WRN protein.

[0891] Experimental instruments

[0892] Experimental Materials

[0893] Experimental methods

[0894] Test compounds were dissolved in DMSO at a stock concentration of 10 mM. Serial dilutions of the compound stock solution were performed using the dose-response program on the Echo instrument. The dilution program consisted of 4 μL of total volume, starting at 10 μM, followed by 3-fold dilutions over 10 concentration points. The total volume of compound and DMSO was 160 nL, with a final DMSO concentration of 0.4%. 2 μL of 2X WRN-ATP mixture (buffer: 25 mM Tris-HCL (PH8.0), 50 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.01% Tween-20, 0.00025% BSA; WRN: 20 nM; ATP: 600 μM) was added to the experimental plate and incubated at room temperature for 3 hours. 2 μL of 2X Hec1 (0.4 nM) was added and incubated at room temperature for 0.5 hours. 4 μL of ADP-Glo ​​reagent (ADP-Glo ​​detection kit) was added and incubated for another 1 hour. 8 μL of Detection reagent (ADP-Glo ​​detection kit) was added and incubated at room temperature for 1 hour. The chemiluminescent signal value was read on Envision. The signal value of the WRN reaction well was defined as the 0% inhibition control, and the signal value of the well without WRN was defined as the 100% inhibition control. The inhibition rate of the compound-treated well was calculated. The IC was calculated using a four-parameter fitting using the inhibition rate. 50 .

[0895] The experimental results are shown in the following table:

[0896] Test Example 2: HCT-116, Caco-2, DLD-1 WRN-KO Cell Proliferation Assay

[0897] Experimental Principle

[0898] The cells used in the experiment are HCT-116, an MSI (microsatellite unstable) cell line, Caco-2, an MSS (microsatellite stable) cell line, and DLD-1WRN-KO, a stable cell line after WRN gene knockout in DLD-1 cells through CRSIPR editing. The 2.0 Luminescent Cell Viability Assay quantifies ATP in living cells and tests the inhibitory effect of test compounds on cell proliferation. The luminescent signal generated by the kit is proportional to the amount of ATP, which is directly proportional to the number of cells.

[0899] Experimental instruments

[0900] Experimental Materials

[0901] HCT-116 cells were cultured in McCoy's 5A medium with 10% FBS, Caco-2 cells in MEM with 20% FBS, and DLD-1WRN-KO cells in RPMI-1640 with 10% FBS. After trypsinization, the cell concentrations were adjusted to 300 / 40 μL / well for HCT-116, 600 / 40 μL / well for Caco-2, and 500 / 40 μL / well for DLD-1WRN-KO in 384-well plates and incubated overnight at 37°C in a 5% CO2 incubator. Test compounds were dissolved in DMSO at a stock concentration of 10 mM. Serial dilutions of the compound stock solution were performed using the dose-response program on the Echo instrument using DMSO. The protocol was as follows: a 40 μL total volume, a starting concentration of 10 μM, three-fold dilutions, and 10 concentration points. The total compound and DMSO volume was 200 nL. After the cell plates were cultured in a cell culture incubator for another 4 days, they were equilibrated to room temperature. 20 μL of CCL reagent was added to each well. After shaking in the dark for 60 minutes, the luminescence signal was read using Envision. The cell control wells were defined as the 0% inhibition control, and the culture medium wells were defined as the 100% inhibition control. The inhibition rate of the sample wells was calculated. The inhibition rate was used to perform a four-parameter fitting to calculate the IC. 50 (XLfit, Formula 205).

[0902] The experimental results are shown in the following table:

[0903] Test Example 3: Pharmacokinetics test in rats

[0904] 1. Test Materials

[0905] SD rats were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0906] NMP (N-methylpyrrolidone), Solutol HS15 (polyethylene glycol 15-hydroxystearate), HP-β-CD (hydroxypropyl-β-cyclodextrin), and verapamil were purchased from Sigma. K2EDTA anticoagulant blood collection tubes were purchased from Jiangsu Xinkang Medical Instrument Co., Ltd.

[0907] 2. Test methods

[0908] 1. Animal Testing

[0909] For each test compound, six male SD rats (200-300 g, 6-8 weeks old) were randomly divided into two groups of three. The first group received the compound via tail vein injection in a vehicle consisting of 5% NMP + 10% Solutol HS15 + 85% water; the second group received the corresponding dose of the compound orally in a vehicle consisting of 10% HP-β-CD. Prior to the experiment, the animals were fasted overnight and given normal water. During the experiment, venous blood was collected from each group of rats before administration and at 0.083 (Group 1 only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The collected whole blood samples were placed in K2EDTA anticoagulant tubes and centrifuged for 5 minutes (4000 rpm, 4°C). Plasma was then collected for analysis. Four hours after administration, the animals were fed and watered normally.

[0910] 2. Sample Processing and Bioanalysis

[0911] Ten μL of rat plasma sample was prepared and protein was precipitated by adding 150 μL of methanol / acetonitrile (1:1, v / v) (containing an internal standard, 10 ng / mL verapamil). After vortexing for 5 minutes, the sample was centrifuged for 5 minutes (14,000 rpm, 4°C). The supernatant was diluted 2-fold with water containing 0.1% formic acid (v / v) and quantified using an LC-MS / MS system (AB Sciex Triple Quad 6500+). Male Sprague-Dawley rat plasma standard curve and quality control samples were also used for sample concentration determination. For the 20x diluted sample, 2 μL of the sample was added to 38 μL of rat blank plasma. After vortexing for 1 minute, protein was precipitated by adding 600 μL of methanol / acetonitrile (1:1, v / v) (containing an internal standard, 10 ng / mL verapamil). The remaining processing steps were the same as above.

[0912] 3. Data Processing

[0913] The pharmacokinetic parameters were calculated using the non-compartmental statistical moment method using Phoenix WinNonlin 8.0 software (Certara, USA).

[0914] 4. Test results

[0915] The results of the rat pharmacokinetic study are shown in the following table.

[0916] PK of the disclosed compounds in rats (intravenous administration)

[0917] PK of the compounds of the present disclosure in rats (oral administration)

[0918] Test Example 4: Pharmacokinetics test in mice

[0919] 1. Test Materials

[0920] Balb / c nude mice and NOD SCID mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0921] NMP (N-methylpyrrolidone), Solutol HS15 (polyethylene glycol 15-hydroxystearate), HP-β-CD (hydroxypropyl-β-cyclodextrin), and verapamil were purchased from Sigma. K2EDTA anticoagulant blood collection tubes were purchased from Jiangsu Xinkang Medical Instrument Co., Ltd.

[0922] 2. Test methods

[0923] 1. Animal Testing

[0924] For each test compound, six female Balb / c nude mice or NOD SCID mice (20-30 g, 4-6 weeks old) were randomly divided into two groups of three. The first group received the compound via tail vein injection in a vehicle consisting of 5% NMP + 10% Solutol HS15 + 85% water; the second group received the corresponding dose of the compound orally in a vehicle consisting of 10% HP-β-CD. Prior to the experiment, the animals were fed and watered normally. During the experiment, venous blood was collected from each group of mice before administration and at 0.083 (Group 1 only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The collected whole blood samples were placed in K2EDTA anticoagulant tubes and centrifuged for 5 minutes (4000 rpm, 4°C). Plasma was then collected for analysis.

[0925] 2. Sample Processing and Bioanalysis

[0926] 10 μL of mouse plasma sample was prepared and protein was precipitated by adding 150 μL of methanol / acetonitrile (1:1, v / v) (containing an internal standard, 10 ng / mL verapamil). After vortexing for 5 minutes, the sample was centrifuged for 5 minutes (14,000 rpm, 4°C). The supernatant was diluted 2-fold with water containing 0.1% formic acid (v / v) and quantified using an AB Sciex Triple Quad 6500+ system. A standard curve and quality control samples of female Balb / c nude mouse plasma were also used for sample concentration determination. For the 20x diluted sample, 2 μL of the sample was added to 38 μL of blank mouse plasma. After vortexing for 1 minute, protein was precipitated by adding 600 μL of methanol / acetonitrile (1:1, v / v) (containing an internal standard, 10 ng / mL verapamil). The remaining processing steps were the same as above.

[0927] 3. Data Processing

[0928] The pharmacokinetic parameters were calculated using the non-compartmental statistical moment method using Phoenix WinNonlin 8.0 software (Certara, USA).

[0929] 4. Test results

[0930] The results of the mouse pharmacokinetic study are shown in the table below.

[0931] PK of the disclosed compounds in mice (intravenous administration)

[0932] PK of the compounds of the present disclosure in mice (oral administration)

[0933] The compounds of the embodiments disclosed herein have higher oral exposure (AUC) and better PK properties.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X 2 and X 4 One is N and the other is C; R 1 is selected from 4-12 membered heterocyclylene, 5-10 membered heteroarylene or C6-C 14 Arylene, the 4-12 membered heterocyclylene, 5-10 membered heteroarylene or C6-C 14 The arylene group is optionally replaced by R 6’ replace; R 6’ Selected from halogen, hydroxyl or C1-C6 alkyl; R 6 Selected from hydrogen, hydroxy, amino, halogen, oxo, cyano, C(O)C3-C 10 Cycloalkyl, C(O)C1-C 10 Alkyl, 5-10 membered heteroaryl, C(O)4-12 membered heterocyclic group, C(O)NHC1-C6 alkyl, C(O)OC3-C 10 Cycloalkyl, C(O)OC1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), C1-C 10 Alkyl, C1-C 10 Alkoxy, -O-C3-C 10 Cycloalkyl, -S-C3-C 10 Cycloalkyl, -O-4-12 membered heterocyclic group, -S-4-12 membered heterocyclic group, -S-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -S(O)-C3-C 10 Cycloalkyl, -S(O)-C1-C 10 Alkyl, -S(O)2-C3-C 10 Cycloalkyl, -S(O)2-C1-C 10 Alkyl, 4-12 membered heterocyclic group, -N=S(O)(C1-C6 alkyl)2, -S(O)(NH)-C3-C 10 Cycloalkyl, -S(O)(NC1-C6 alkyl)-C3-C 10 Cycloalkyl, -S(O)(NH)-C1-C 10 Alkyl or -S(O)(NC1-C6 alkyl)-C1-C 10 Alkyl, the C(O)C3-C 10 Cycloalkyl, C(O)C1-C 10 Alkyl, 5-10 membered heteroaryl, C(O)4-12 membered heterocyclic group, C(O)NHC1-C6 alkyl, C(O)OC3-C 10 Cycloalkyl, C(O)OC1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), C1-C 10 Alkyl, C1-C 10 Alkoxy, -O-C3-C 10 Cycloalkyl, -S-C3-C 10 Cycloalkyl, -O-4-12 membered heterocyclic group, -S-4-12 membered heterocyclic group, -S-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -S(O)-C3-C 10 Cycloalkyl, -S(O)-C1-C 10 Alkyl, -S(O)2-C3-C 10 Cycloalkyl, -S(O)2-C1-C 10 Alkyl, 4-12 membered heterocyclic group, -N=S(O)(C1-C6 alkyl)2, -S(O)(NH)-C3-C 10 Cycloalkyl, -S(O)(NC1-C6 alkyl)-C3-C 10 Cycloalkyl, -S(O)(NH)-C1-C 10 Alkyl or -S(O)(NC1-C6 alkyl)-C1-C 10 The alkyl group is optionally replaced by R 6a replace; R 6a Selected from oxo, halogen, cyano, amino, OH, C1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), NH(C3-C6 cycloalkyl), N(C1-C6 alkyl)(C3-C6 cycloalkyl), C1-C6 alkoxy, 4-12 membered heterocyclyl, C3-C 10 Cycloalkyl or COOH, the C1-C6 alkyl, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), NH(C3-C6 cycloalkyl), N(C1-C6 alkyl)(C3-C6 cycloalkyl), C1-C6 alkoxy, 4-12 membered heterocyclyl or C3-C 10 The cycloalkyl group is optionally replaced by R 6b replace; R 6b is selected from deuterium, halogen, oxo, hydroxy, amino, cyano, N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), C1-C6 alkyl or C1-C6 alkoxy, wherein the N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 6c replace; R 6c is selected from halogen, hydroxy, amino or cyano; R 2 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally replaced by R 2a replace; R 2a is selected from halogen, C1-C6 alkyl, SF5 or C(O)H, wherein the C1-C6 alkyl is optionally substituted with halogen; R 3 is selected from C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally replaced by R 3a replace; R 3a Selected from halogen, hydroxy or C1-C4 alkyl; e is a single bond or a double bond, When e is a single bond, Y is N, R 52 and R 53 are each independently selected from hydrogen, halogen or C1-C3 alkyl, or R 52 and R 53 and the atoms to which they are connected together form a C3-C6 cycloalkyl group; or Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C6 cycloalkyl group; When e is a double bond, Y is C, R 52 and R 53 Each is independently selected from hydrogen, halogen or C1-C3 alkyl; R 4 Selected from R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 Each is independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy optionally substituted by halogen; Provided that the compound is not:

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 2 C, X 4 N; or, X 2 N, X 4 For C.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein: R 1 is selected from 4-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene, wherein the 4-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene is optionally replaced by R 6’ replace; Or, where R 1 is selected from 6-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene, wherein the 6-10 membered heterocyclylene, 5-6 membered heteroarylene or phenylene is optionally replaced by R 6’ replace; Or, where R 1 Selected from phenylene, pyridylene, thiazolylene, morpholinylene, dihydropyranylene, tetrahydropyridylene, The phenylene, pyridylene, thiazolyl, morpholinyl, dihydropyranyl, tetrahydropyridyl, Optional R 6’ Substituted, where R 1 in Indicates that X 2 connect.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 6 is selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl, wherein the C1-C8 alkyl, C1-C8 alkoxy, -O-4-12 membered heterocyclyl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl is optionally replaced by R 6a replace; Or, where R 6 is selected from hydrogen, hydroxy, methoxy, methyl, isopropyl, azetidinyl, cyclobutyl, cyclopropyl or O-azetidinyl, wherein the methoxy, methyl, isopropyl, azetidinyl, cyclobutyl, cyclopropyl or O-azetidinyl is optionally replaced by R 6a replace.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 6a is selected from halogen, C1-C6 alkyl, N (C1-C6 alkyl) 2 or 4-12 membered heterocyclic group, wherein the C1-C6 alkyl, N (C1-C6 alkyl) 2 or 4-12 membered heterocyclic group is optionally replaced by R 6b replace; Or, where R 6a is selected from halogen, C1-C3 alkyl, N (C1-C3 alkyl) 2 or 4-7 membered heterocyclic group, wherein the C1-C3 alkyl, N (C1-C3 alkyl) 2 or 4-7 membered heterocyclic group is optionally replaced by R 6b replace; Or, where R 6a Selected from fluorine, N(CH3)2, N(CH3)(CH(CH3)2), ethyl, azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, The N(CH3)2, N(CH3)(CH(CH3)2), ethyl, azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, Optional R 6b replace.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 6b is selected from deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 6c replace.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 6c Selected from halogen.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 6 Selected from hydrogen, methoxy, methyl, isopropyl, CHF2, cyclopropyl, 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 6’ is selected from halogen, hydroxyl or C1-C3 alkyl; or, wherein, R 6’ is selected from fluorine, chlorine, hydroxy or methyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 is selected from phenyl or 8-10 membered heteroaryl, wherein the phenyl or 8-10 membered heteroaryl is optionally replaced by R 2a replace.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 2a is selected from halogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by halogen.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R 3 is selected from C1-C4 alkyl or C3-C4 cycloalkyl, wherein the C3-C4 cycloalkyl is optionally replaced by R 3a replace.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 3a Selected from halogen or C1-C4 alkyl.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein e is a single bond or a double bond, When e is a single bond, Y is N, R 52 and R 53 are each independently selected from hydrogen or C1-C3 alkyl, or R 52 and R 53 and the atoms to which they are connected together form a C3-C4 cycloalkyl group; or Y is CR 51 ,R 51 and R 52 and the atoms to which they are attached together form a C3-C4 cycloalkyl group; When e is a double bond, Y is C, R 52 and R 53 Each is independently selected from hydrogen, halogen or C1-C3 alkyl.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 4 Selected from 16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein: R 10 、R 11 、R 12 、R 13 、R 14 Each is independently selected from hydrogen or C1-C4 alkyl.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein The compound of formula (I) is selected from the compounds of formula (II-1): Among them, e, R 1 、R 2 、R 3 、R 4 、R 52 、R 53 、R 6 Or Y or as defined in any one of claims 1-16.

18. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein The compound of formula (I) is selected from the compounds of formula (II-2): Among them, e, R 2 、R 3 、R 4 、R 52 、R 53 、R 6 、R 6’ Or Y is as defined in any one of claims 1 to 17, and m is selected from 0, 1, 2, 3 or 4.

19. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound of formula (I) is selected from the following compounds:

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

21. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for inhibiting WRN.

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