Sulfonyl compound and use thereof

Abstract

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

Description

Sulfonyl compounds and their applications

[0001] Cross-reference to related applications

[0002] This application claims priority and benefits to the following Chinese patent applications filed with the China National Intellectual Property Administration: Chinese Patent Application No. 202410812439.8, filed June 21, 2024; Chinese Patent Application No. 202411083299.1, filed August 8, 2024; Chinese Patent Application No. 202411385352.3, filed September 30, 2024; and Chinese Patent Application No. 202510050856.8, filed January 13, 2025. The entire contents of the above patent applications are incorporated herein by reference. Technical Field

[0003] This disclosure relates to sulfonyl compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof, methods of their preparation, pharmaceutical compositions containing them, and their use as WRN inhibitors in the prevention or treatment of related diseases. Background Technology

[0004] Helicases are a class of enzymes that untangle double-stranded nucleotides. They utilize the energy released during the hydrolysis of nucleoside triphosphates to move along the nucleic acid chain, thereby untangling and separating the nucleic acid double strands. As representatives 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 genome integrity.

[0005] RecQ family helicases are highly conserved throughout evolution, and their functions are involved in a variety of DNA metabolic processes, playing a crucial role in maintaining genome stability. The loss of function of BLM, WRN, and RecQ4, three of the five RecQ family helicases in humans, leads to BLM syndrome, WRN syndrome, and Rothmund-Thomson syndrome, respectively. These diseases all exhibit high genomic instability, chromosomal abnormalities, and susceptibility to DNA damage at the molecular level.

[0006] WRN and RecQ1 are two of the most representative RecQ helicases. WRN includes not only its unwinding domain but also an exonuclease domain. Werner syndrome (WS) is an autosomal recessive genetic disorder characterized by accelerated clinical aging, resulting in a lifespan of less than 50 years. WS helicase nuclease (WRN) is involved in many important pathways, including DNA replication, recombination, and repair. WRN can unwind non-canonical secondary DNA structures encountered during replication and recombination; mutations in WRN can cause chromosomal instability disorders such as Werner syndrome. Under normal circumstances, WRN depletion leads to DNA double-strand breaks in MSI cells, resulting in cell cycle arrest and / or apoptosis. Studies have shown a strong synthetic lethal 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 MLH1 loss is associated with microsatellite instability (MSI).

[0007] Microsatellites are simple repetitive sequences of less than 10 nucleotides in the genome. Defects in DNA mismatch repair (MMR) caused by gene mutations or promoter hypermethylation can lead to hypermutations in nucleotide repeat regions (microsatellites), a condition known as microsatellite instability (MSI). MSI can promote the development of various cancers, including colon cancer (15%), gastric cancer (22%), endometrial cancer (20%-30%), and ovarian cancer (12%), with 45%-60% of these not responding to immune checkpoint blockade. Therefore, MSI tumors require novel treatment approaches. In two genome-wide gene inactivation studies using CRISPR or RNA interference, wRN was identified as the most significant dependency in MSI-H cells, and this dependency was associated with unwinding activity but not with the nuclease function of wRN. These findings, coupled with the good tolerance of microsatellite stable (MSS) cancer cells to wRN silencing, 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] This disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof or stereoisomers thereof.

[0010] in,

[0011] X 3 Selected from O, NH or NR 5 ;

[0012] R 5 Selected from cyano, C(=O)C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C(=O)C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 5a replace;

[0013] R 5a Selected from halogen, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy;

[0014] When X 3 When selected from O, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 4-6 membered heterocyclic group or C1-C6 alkyl group, wherein the 4-6 membered heterocyclic group is optionally R 10a The C1-C6 alkyl group is replaced by R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace;

[0015] When X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or, the R 10 R 5 Together with the atoms bonded to it, they form 4-10 membered heterocyclic groups, wherein the 4-10 membered heterocyclic groups are optionally subjected to R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace;

[0016] R 10a R 11a Each is independently selected from halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0017] R 8 R 9Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C(O)C1-C6 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or C(O)C1-C6 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally subjected to R 9a replace;

[0018] R 8a R 9a Each is independently selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy or C1-C6 alkyl;

[0019] L 2 Selected from -C(=O)NH-, -C(=S)NH-, -S(=O)2NH-, 1,2,3-triazolyl, oxadiazolyl, imidazolyl, tetrazolyl, pyrazolyl, -NHC(=O)NH-, -NHC(=O)O-, -CH(CF3)NH- or

[0020] R 3 Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 5-12 membered heterocyclic groups, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 5-12 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are selectively coated with R. 3a replace;

[0021] R 3a Selected from halogen, cyano, hydroxy, amino, carboxyl, oxo, -S-C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -S-C1-C6 alkyl, -O-C3-C6 cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2 or phenoxy, wherein the amino, -S-C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -S-C1-C6 alkyl, -O-C3-C6 cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2 or phenoxy is optionally R 3b replace;

[0022] R 3b Selected from halogens or C1-C6 alkyl groups;

[0023] L 1Selected from bonds, O, S, NH, CH2, or OCH2;

[0024] R 1 Selected from hydrogen, C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group are optionally replaced by R 1a replace;

[0025] R 1a Selected from halogen, deuterium, cyano, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, oxo, -S-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl or carboxyl;

[0026] X is selected from N or CR x ;

[0027] Y is selected from N or CR y ;

[0028] Z is selected from N or CR. z ;

[0029] Alternatively, Y and Z, along with their linked bonds, form a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycle, which is optionally composed of R. 7 replace;

[0030] The condition is that X, Y, and Z are not all N at the same time;

[0031] R 7 Selected from halogens, cyano groups, amino groups, NHC(=O)C1-C6 alkyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups; or two R groups attached to adjacent ring atoms. 7 Together with the atoms they are attached to, they form C5-C. 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 membered heterocyclic rings or 5-10 membered heteroaromatic rings, wherein C5-C 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 quinary heterocyclic rings, or 5-10 quinary heterocyclic rings can be selected by R. 7a replace;

[0032] R 7a Selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0033] R x Ry and R z Each is independently selected from H, halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0034] R 2 Selected from halogen, cyano, C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, wherein the C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, optionally with R 2a Replace; or R 2 Y and the carbon atoms they are attached to form C6-C. 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles, wherein the C6-C 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles may be selectively replaced by R. 6 replace;

[0035] R 2a Selected from hydroxyl, oxo, halogen, C1-C6 alkyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, amino, carboxyl, -S-C1-C6 alkyl, -S-C3-C8 cycloalkyl, or -O-C3-C8 cycloalkyl, wherein the C1-C6 alkyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, -S-C1-C6 alkyl, -S-C3-C8 cycloalkyl, or -O-C3-C8 cycloalkyl is optionally R 2b replace;

[0036] R 2b Selected from halogens or C1-C6 alkyl groups;

[0037] R6 Selected from halogens, cyano groups, amino groups, NHC(=O)C1-C6 alkyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups; or two R groups attached to adjacent ring atoms. 6 Together with the atoms they are attached to, they form C5-C. 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 membered heterocyclic rings or 5-10 membered heteroaromatic rings, wherein C5-C 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 quinary heterocyclic rings, or 5-10 quinary heterocyclic rings can be selected by R. 6a replace;

[0038] R 6a It is selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0039] In some implementation schemes, when X 3 When selected from O, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 Or a 4-membered heterocyclic group, wherein the 4-membered heterocyclic group is optionally R 10a Replace; when X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a replace.

[0040] In some implementation schemes, X 3 Selected from O, NH or NR 5 ;

[0041] When X 3 When selected from O, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 4-6 membered heterocyclic group or C1-C6 alkyl group, wherein the 4-6 membered heterocyclic group is optionally R 10a The C1-C6 alkyl group is replaced by R 10a replace;

[0042] When X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or, the R 10 R 5 Together with the atoms bonded to it, they form 4-10 membered heterocyclic groups, wherein the 4-10 membered heterocyclic groups are optionally subjected to R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace;

[0043] L 2 Selected from -C(=O)NH- or -C(=O)N(C1-C3 alkyl)-;

[0044] L 1 Selected from key or O;

[0045] R 2 Selected from C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, wherein the C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, optionally with R 2a Replace; or R 2 Y and the carbon atoms they are attached to form C6-C. 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles, wherein the C6-C 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles may be selectively replaced by R. 6 replace.

[0046] In some implementation schemes, X 3 Selected from O, NH or NR 5 ;

[0047] When X 3 When selected from O, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 4-6 membered heterocyclic group or C1-C6 alkyl group, wherein the 4-6 membered heterocyclic group is optionally R 10a The C1-C6 alkyl group is replaced by R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace;

[0048] When X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace;

[0049] R 7 Selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0050] R 6 It is selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0051] In some implementation schemes, yes

[0052] In some implementation schemes, yes

[0053] In some implementation schemes, yes

[0054] In some implementation schemes, X 3 Selected from O, NH or NR 5 ;R 10 Selected from NR 8 R 9 .

[0055] In some implementation schemes, X 3 Selected from O.

[0056] In some implementation schemes, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from C1-C3 alkyl, 4-membered heterocyclic or NR 8 R 9 The C1-C3 alkyl group is R 10a The 4-membered heterocyclic group is optionally replaced by R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-membered heterocyclic group, which is optionally subjected to R 11a replace.

[0057] In some implementation schemes, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from C1-C6 alkyl, 4-6 membered heterocyclic or NR 8 R 9 The C1-C3 alkyl group is R 10a Replace; or, R 10 R 11 Together with the atoms attached to it, they form 4-6 member heterocyclic groups.

[0058] In some implementation schemes, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from C1-C3 alkyl, 4-membered heterocyclic or NR 8 R 9 The C1-C3 alkyl group is R 10a Replace; or, R 10 R 11 Together with the atoms attached to it, they form a 4-membered heterocyclic group.

[0059] In some implementation schemes, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from methyl, aziridine, oxetidine or NR 8 R9 The methyl group is R 10a The substituted nitrogen-containing heterocyclic butyl group or oxocyclic butyl group is optionally replaced by R. 10a Replace; or, R 10 R 11 Together with the atoms connected to it, they form

[0060] In some implementation schemes, R 10a It is selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl or C1-C6 alkoxy.

[0061] In some implementation schemes, R 10a It is selected from C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0062] In some implementation schemes, R 10a Selected from C3-C4 cycloalkyl groups.

[0063] In some implementation schemes, R 10a Selected from cyclopropyl.

[0064] In some implementation schemes, X 3 Selected from O, R 10 Selected from NR 8 R 9 .

[0065] In some implementation schemes, R 8 R 9 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or C(O)C1-C3 alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, or C(O)C1-C3 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally subjected to R 9a replace.

[0066] In some implementation schemes, R 8 R 9 Each is independently selected from hydrogen, C1-C3 alkyl, cyclopentyl, or C(O)C1-C3 alkyl, wherein the C1-C3 alkyl, cyclopentyl, or C(O)C1-C3 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-membered heterocyclic group, which is optionally R 9a replace.

[0067] In some implementation schemes, R 8R 9 Each is independently selected from hydrogen, methyl, ethyl, cyclopentyl, or C(O)CH3, wherein the methyl, ethyl, cyclopentyl, or C(O)CH3 is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a nitrogen-containing heterocyclic butyl group, wherein the nitrogen-containing heterocyclic butyl group is optionally R 9a replace.

[0068] In some implementation schemes, R 8a Selected from C1-C6 alkoxy groups.

[0069] In some implementation schemes, R 8a Selected from C1-C3 alkoxy groups.

[0070] In some implementation schemes, R 8a Selected from methoxy groups.

[0071] In some implementation schemes, Selected from

[0072] In some implementation schemes, when X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace.

[0073] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a replace.

[0074] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 10a Replace; or, the R 10R 5 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 10a replace.

[0075] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 10a replace.

[0076] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C3 alkyl groups; or, the R 10 R 5 Together with the atoms attached to it, they form a 6-membered heterocyclic group.

[0077] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C3 alkyl groups.

[0078] In some implementation schemes, X 3 Selected from NH or NR 5 ;R 10 Selected from methyl, or R 10 R 5 Together with the atoms connected to it, they form

[0079] In some implementation schemes, R 5 Selected from cyano, C(=O)C1-C6 alkyl, or C1-C6 alkyl, wherein the C(=O)C1-C6 alkyl or C1-C6 alkyl is optionally R 5a replace.

[0080] In some implementation schemes, R 5 Selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally R 5a Replace; or, the R 5 R 10 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 10a replace.

[0081] In some implementation schemes, R 5 Selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally R 5a replace.

[0082] In some implementation schemes, R 5 Selected from C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally R 5a replace.

[0083] In some implementation schemes, R 5 Selected from C1-C3 alkyl or C3-C4 cycloalkyl, or R 5 R 10 Together with the atoms attached to it, they form a 6-membered heterocyclic group.

[0084] In some implementation schemes, R 5 It is selected from C1-C3 alkyl or C3-C4 cycloalkyl.

[0085] In some implementation schemes, R 5 Selected from C1-C3 alkyl groups.

[0086] In some implementation schemes, R 5 Selected from methyl or cyclopropyl, or R 5 R 10 Together with the atoms connected to it, they form

[0087] In some implementation schemes, X 3 Selected from NH, R 10 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a replace.

[0088] In some implementation schemes, X 3 Selected from NH, R 10 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 10a replace.

[0089] In some implementation schemes, X 3 Selected from NH, R 10 Selected from C1-C3 alkyl groups.

[0090] In some implementation schemes, Selected from

[0091] In some implementation schemes, Selected from

[0092] In some implementations, L 2Selected from -C(=O)NH-, -C(=S)NH-, -S(=O)2NH-, -NHC(=O)NH-, -NHC(=O)O- or -CH(CF3)NH-.

[0093] In some implementations, L 2 Selected from -C(=O)NH- or -C(=O)N(C1-C3 alkyl)-.

[0094] In some implementations, L 2 Selected from -C(=O)NH-.

[0095] In some implementation schemes, R 3 Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are selectively coated with R. 3a replace.

[0096] In some implementation schemes, R 3 Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 5-6 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 5-6 membered heterocyclic group is optionally R 3a replace.

[0097] In some implementation schemes, R 3 Selected from C3-C8 cycloalkyl groups, wherein the C3-C8 cycloalkyl group is optionally R 3a replace.

[0098] In some implementation schemes, R 3 Selected from C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl group is optionally R 3a replace.

[0099] In some implementation schemes, R 3 Selected from cyclopropyl.

[0100] In some implementation schemes, R 3 The bonded C atoms have an S configuration.

[0101] In some implementations, L 1 Selected from key or O.

[0102] In some implementations, L 1 It is O.

[0103] In some implementation schemes, R 1 Selected from C3-C8 cycloalkyl, C6-C 10aryl or 5-6-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C 10 Aryl or 5-6 quinone heteroaryl groups are selectively substituted with R. 1a replace.

[0104] In some implementation schemes, R 1 Selected from C6-C 10 Aryl.

[0105] In some implementation schemes, R 1 Selected from phenyl.

[0106] In some implementations, X is selected from N or CR. x Y is selected from N or CR y Z is selected from N or CR z The condition is that X, Y, and Z are not all N at the same time.

[0107] In some implementations, X is selected from N, Y is selected from N, and Z is selected from CR. z .

[0108] In some implementation schemes, R 7 It is selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0109] In some implementation schemes, R z Selected from H, halogen, amino, C1-C6 alkyl or NHC(=O)C1-C6 alkyl.

[0110] In some implementation schemes, R z Selected from H.

[0111] In some implementations, X is selected from N, Y is selected from N, and Z is selected from CH.

[0112] In some implementation schemes, R 2 Selected from C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, wherein the C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, optionally with R 2a Replace; or R 2 Y and the carbon atoms they are attached to form C6-C. 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles, wherein the C6-C 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-6 membered heteroaromatic rings, or 5-6 membered heterocycles may be selectively replaced by R. 6 replace.

[0113] In some implementation schemes, R 2 Selected from C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, or C1-C6 alkoxy is optionally R 2a replace.

[0114] In some implementation schemes, R 2 Selected from C1-C6 alkyl, amino, -S-C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, amino, -S-C1-C6 alkyl, or C1-C6 alkoxy is optionally R 2a replace.

[0115] In some implementation schemes, R 2 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 2a replace.

[0116] In some implementation schemes, R 2 Selected from C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally R 2a replace.

[0117] In some implementation schemes, R 2 Selected from methyl, ethyl, or tert-butyl, wherein the methyl, ethyl, or tert-butyl group is optionally R 2a replace.

[0118] In some implementation schemes, R 2 Selected from C1-C4 alkyl groups.

[0119] In some implementation schemes, R 2a Selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino, carboxyl, or -S-C1-C6 alkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, amino, or -S-C1-C6 alkyl is optionally R 2b replace.

[0120] In some implementation schemes, R 2a Selected from halogens or C3-C4 cycloalkyl groups.

[0121] In some implementation schemes, R 2a Selected from fluorine or cyclopropyl.

[0122] In some implementation schemes, R 2a Selected from halogens.

[0123] In some implementation schemes, R 6 It is selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0124] In some embodiments, the compounds of formula (I) of this disclosure, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, are selected from the compounds of formula (IA), or pharmaceutically acceptable salts thereof, or stereoisomers thereof:

[0125] Among them, R 10 X 3 R 3 L 2 L 1 R 1 R 2 X, Y, and Z are as defined above.

[0126] In some embodiments, the compound of formula (I) of this disclosure, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is selected from the compound of formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0127] Among them, R 8 R 9 X 3 R 3 L 2 L 1 R 1 R 2X, Y, and Z are as defined above.

[0128] In some embodiments, the compounds of formula (I) of this disclosure, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, are selected from the compounds of formula (III), or pharmaceutically acceptable salts thereof, or stereoisomers thereof:

[0129] Among them, R 10 R 11 X 3 R 3 L 2 L 1 R 1 R 2 X, Y, and Z are as defined above.

[0130] In some embodiments, the compounds of formula (I) of this disclosure, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, are selected from the compounds of formula (IV), or pharmaceutically acceptable salts thereof, or stereoisomers thereof:

[0131] Among them, R 10 R 11 R 3 L 2 L 1 R 1 R 2 X, Y, and Z are as defined above.

[0132] In some embodiments, the compounds of formula (I) of this disclosure are selected from the following compounds:

[0133] In some embodiments, the compounds of formula (I) of this disclosure are selected from the following compounds:

[0134] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a pharmaceutically acceptable excipient.

[0135] On the other hand, this disclosure provides a method for inhibiting WRN, which includes the step of contacting a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof, with WRN.

[0136] On the other hand, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof, which is used as a WRN inhibitor.

[0137] On the other hand, this disclosure provides a method for treating diseases mediated by WRN helicase in mammals, comprising administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof.

[0138] On the other hand, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of WRN helicase-mediated diseases.

[0139] On the other hand, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof, in the prevention or treatment of WRN helicase-mediated diseases.

[0140] On the other hand, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof or stereoisomers thereof, or pharmaceutical compositions thereof, for the prevention or treatment of WRN helicase-mediated diseases.

[0141] In some implementations, WRN helicase-mediated disease is a disease that inhibits WRN helicase.

[0142] In some implementations, the disease mediated by WRN helicase is selected from cancer or Werner syndrome.

[0143] In some implementations, the diseases mediated by WRN helicase are selected from cancer.

[0144] In some implementations, the cancer is colorectal cancer.

[0145] Terminology Definitions and Explanations

[0146] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0147] In this article Indicates the connection site.

[0148] Unless otherwise specified, use wedge keys and virtual wedge keys. The absolute configuration representing the center of a solid.

[0149] In this article The representation is either (Z) configuration or (E) configuration, for example... The representative is the (Z) configuration. or (E) configuration

[0150] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0151] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0152] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups or other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents, and mixtures thereof, are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0153] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted.

[0154] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0155] When any variable (e.g., R) a R b When a group 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 surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0156] When one of the variables is selected as a chemical bond or does not exist, it means that the two groups it is connected to are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0157] If the linking group mentioned in this article does not specify its linking direction, then its linking direction is arbitrary. For example, when the structural unit... L in 1 When selected from "C1-C3 alkylene-O", L 1 Both loops Q and R can be connected in a left-to-right direction. 1 Composed of "cyclo-Q-C1-C3 alkylene-OR" 1 Alternatively, rings Q and R can be connected from right to left. 1 Composed of "cyclo-QO-C1-C3 alkylene-R" 1 ".

[0158] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0159] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1The alkyl group can be straight-chain or branched. The term "C1-C" refers to a hydrocarbon group. 10 "Alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups 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 as referring to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including but 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-C4 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1, 2, or 3 carbon atoms. The "C1-C6 alkyl" 10 "alkyl" can include the range of "C1-C8 alkyl", "C1-C6 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" can further include "C1-C3 alkyl".

[0160] The term "halogenated alkyl" refers to a group formed by replacing one or more hydrogen atoms on an alkyl group with a halogen.

[0161] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it 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 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" can further include "C1-C3 alkoxy".

[0162] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10"Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 The term "alkenyl" may include "C2-C8 alkenyl," preferably "C2-C6 alkenyl," further preferably "C2-C4 alkenyl," and even more preferably C2 or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc.

[0163] The term "cycloalkyl" refers to a fully saturated carbon ring existing 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" is also used. 10 "Cycloalkyl" can be understood as referring to a saturated monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of cycloalkyl 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, etc. The term "C3-C6 cycloalkyl" can be understood as referring to a saturated monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, or 6 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc. The term "C3-C4 cycloalkyl" can be understood as referring to a saturated monocyclic, fused, spirocyclic, or bridged ring having 3 or 4 carbon atoms. The term "C3-C6 cycloalkyl" can be understood as referring to a saturated monocyclic, fused, spirocyclic, or bridged ring having 3 or 4 carbon atoms. 10 "Cycloalkyl" can include "C3-C8 cycloalkyl" and "C3-C6 cycloalkyl".

[0164] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, this carbon ring is typically a 5- to 10-membered ring. The term "C5-C" is also used. 10"Cycloalkenyl" can be understood as referring to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. The term "C5-C8 cycloalkenyl" can be understood as referring to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5, 6, 7, or 8 carbon atoms. The term "C5-C6 cycloalkenyl" can be understood as referring to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring, having 5 or 6 carbon atoms. 10 "Cycloalkenyl" can include "C5-C8 cycloalkenyl" and "C5-C6 cycloalkenyl".

[0165] The term "heterocyclic group" refers to a fully saturated or partially saturated monocyclic, fused, spirocyclic, or bridged ring group containing 1-5 heteroatoms or heterogroups (i.e., groups containing heteroatoms). These "heteroatoms or heterogroups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. The term "4-18 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 membered ring atoms, and its ring atoms contain 1-5 heteroatoms or heterogroups independently selected from those described above. The term "4-12 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and whose ring atoms contain 1-5 independently selected heteroatoms or heteroatomic groups as described above. "4-10 membered heterocyclic group" includes "4-7 membered heterocyclic group", wherein specific examples of 4 membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxacyclobutane; specific examples of 5 membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; and specific examples of 7 membered heterocyclic groups include, but are not limited to, diazacycloheptane. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazinolo-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 can be a benzofused cyclic group or a heteroaromatic fused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl, etc. The heterocyclic group can also be a tricyclic group. "4-10 membered heterocyclic group" can include the ranges of "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocyclic alkyl group", "5-10 membered heterocyclic alkyl group", "4-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", and "6-8 membered heterocyclic alkyl group". "4-7 membered heterocyclic group" can further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic alkyl group", "4-6 membered heterocyclic alkyl group", and "5-6 membered heterocyclic alkyl group".Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0166] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 20 "Aryl" can be understood as an aryl group having 6 to 20 carbon atoms. Specifically, it refers to a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or rings having 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups; or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. The term "C6-C" is used. 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. Specifically, it refers to a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0167] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. The term "5-10-membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. "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 it contains 1 to 3, preferably 1 to 2, heteroatoms independently selected from N, O and S.

[0168] 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., nucleophilic substitution). For example, representative leaving groups include, but are not limited to, trifluoromethanesulfonates, chlorine, bromine, iodine, sulfonate groups (e.g., methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates), or acyloxy groups (e.g., acetoxy, trifluoroacetoxy).

[0169] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0170] The term "hydroxyl group" refers to the -OH group.

[0171] The term "amino" refers to the -NH2 group.

[0172] 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, subtypes, and homologues of full-length wild-type WRN. "WRN-mediated diseases or conditions" includes diseases or conditions treated by WRN inhibition, such as cancer.

[0173] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0174] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0175] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0176] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0177] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0178] The word “comprise” or “include” and its English variants such as comprises or comprising can be understood as having an open, non-exclusive meaning, that is, “including but not limited to”.

[0179] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0180] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 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. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0181] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0182] Typical routes of administration for the disclosed compound or its pharmaceutically acceptable salt or its stereoisomer or pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous or intravenous administration.

[0183] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0184] In some embodiments, the pharmaceutical composition is in an 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 this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0185] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0186] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0187] In all methods of administration of the compound of general formula I described herein, the daily dose may be from 0.01 mg / kg to 100 mg / kg body weight, in the form of single or separate doses.

[0188] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0189] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0190] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups. For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this disclosure are incorporated herein by reference in their entirety.

[0191] The following abbreviations are used in this disclosure: Detailed Implementation

[0192] The invention is described in detail below with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail, 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 of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0193] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0194] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0195] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0196] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0197] Example 1: Synthesis of (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-3-aminosulfonylallyl)-4-phenoxypyrimidine-5-carboxamide (Compound 1)

[0198] Step 1: Synthesis of Compound 1b

[0199] Compound 1a (21.5 g, 99.89 mmol) was dissolved in tetrahydrofuran (100 mL) under argon protection, cooled in an ice bath at 0–5 °C with stirring. Then, Red-Al (70% toluene solution, 100 mL, 349.6 mmol) was slowly added dropwise to the system. The mixture was kept at 0–5 °C with stirring until fully reacted. The reaction was monitored by TLC until complete. The reaction was quenched with methanol, and potassium sodium tartrate (40 mL, 1 g / mL) was added simultaneously. The mixture was allowed to separate into layers. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium bicarbonate solution and once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give compound 1b (20.1 g).

[0200] Step 2: Synthesis of compound 1c

[0201] Compound 1b (5.0 g, 24.89 mmol) was dissolved in DCM (150 mL), and sodium bicarbonate solid (12.55 g, 149.36 mmol) was added. The system was protected with argon and cooled to 0–5 °C with stirring. Then, DMP (21.12 g, 49.79 mmol) was added in portions. The reaction mixture was kept at 0–5 °C with stirring until fully reacted. The reaction was detected by TLC. The system was diluted with DCM, washed twice with saturated sodium thiosulfate solution, washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was mixed with silica gel and purified by column chromatography with gradient elution (0–35% EA) to give compound 1c (1.67 g).

[0202] Step 3: Synthesis of compound 1f

[0203] Compound 1d (12.5 g, 124.80 mmol) and compound 1e (27 g, 133.5 mmol) were dissolved in ethanol (150 mL) and cooled to 0°C. Sodium ethoxide (25.5 g, 374 mmol) was then added. The resulting reaction mixture was allowed to react completely at 90°C. After cooling to room temperature, ice water (200 mL) was added, and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1f (14.2 g), the crude product. The crude product was used directly in the next step.

[0204] Step 4: Synthesis of 1g of compound

[0205] Compound 1f (12.5 g, 55.7 mmol) was dissolved in phosphorus oxychloride (70 mL). The resulting mixture was reacted thoroughly at 80°C. The volatiles were removed under reduced pressure to obtain compound 1 g (24 g, crude product). The crude product was used directly in the next step.

[0206] Step 5: Synthesis of Compound 1i

[0207] Compound 1 g (10 g, crude product) and phenol 1 h (2.33 g, 24.7 mmol) were dissolved in ACN (70 mL). Potassium carbonate (8.54 g, 61.8 mmol) was then added. The resulting reaction solution was stirred at 80 °C until fully reacted. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0%–50%) to give compound 1i (3.0 g).

[0208] Step Six: Synthesis of Compound 1j

[0209] Compound 1i (3.0 g, 10 mmol) was dissolved in THF (30 mL) and water (8 mL). Lithium hydroxide (598 mg, 25 mmol) was then added. The resulting reaction mixture was stirred thoroughly at room temperature. The solution was diluted with water (20 mL) and the pH was adjusted to 2-3 with 1 N hydrochloric acid. Extraction was performed with ethyl acetate (20 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1j (2.8 g, crude). The crude product was used directly in the next step.

[0210] Step 7: Synthesis of Compound 1l

[0211] Triethylamine (2.58 g, 25.51 mmol, 3.56 mL) and methanesulfonic anhydride (2.54 g, 14.58 mmol) were added to a solution of compound 1k (1.0 g, 7.29 mmol) in dichloromethane (15 mL) at 0 °C. The mixture was stirred at room temperature until fully reacted. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and purified by column chromatography to give compound 1l (1.5 g).

[0212] Step 8: Synthesis of Compound 1m

[0213] Di-tert-butyl dicarbonate (760.4 mg, 3.48 mmol, 800.41 μL) and 4-dimethylaminopyridine (425.6 mg, 3.48 mmol) were added to a solution of compound 1L (500.0 mg, 2.32 mmol) in 8 mL of dichloromethane. The mixture was stirred at room temperature until fully reacted. The reaction solution was evaporated to dryness and purified by column chromatography to give compound 1M (657 mg).

[0214] Step Nine: Synthesis of Compound 1n

[0215] A tetrahydrofuran solution of potassium tert-butoxide (1M, 2.98 mL, 2.98 mmol) was added to a tetrahydrofuran solution of compound 1m (313.0 mg, 992.44 μmol) in 7 mL. The mixture was reacted at -78 °C for 1 h. Then, a tetrahydrofuran solution of compound 1c (237.3 mg, 1.19 mmol) in 0.5 mL was slowly added, and the mixture was slowly heated to room temperature with stirring until fully reacted. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give compound 1n (478 mg).

[0216] Step 10: Synthesis of Compound 1o

[0217] Triethylamine (234.7 mg, 2.32 mmol) and methanesulfonyl chloride (126.0 mg, 1.10 mmol) were added to a 5 mL solution of compound 1n (478.0 mg, 928.70 μmol) in dichloromethane. The mixture was stirred at room temperature until fully reacted. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give compound 1o (452 ​​mg).

[0218] Step 11: Synthesis of compound 1p

[0219] p-Toluenesulfonic acid (470.2 mg, 2.73 mmol) was added to a solution of compound 1o (452.0 mg, 910.16 μmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature until fully reacted. The reaction solution was concentrated to give compound 1p (260 mg).

[0220] Step 12: Synthesis of Compound 1r

[0221] N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (30.9 mg, 81.99 μmol) and N,N-diisopropylethylamine (28.3 mg, 218.63 μmol) were added to a solution of compounds 1p (54.0 mg, 182.20 μmol) and 1j (14.9 mg, 54.66 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into water, extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give compound 1r (20 mg).

[0222] Step Thirteen: Synthesis of Compound 1

[0223] Cerium ammonium nitrate (288.8 mg, 544.79 μmol) was added to a mixed solution of compound 1r (100.0 mg, 181.60 μmol) in acetonitrile (1.5 mL) and water (1.5 mL). The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into a saturated sodium chloride solution and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain compound 1 (7 mg).

[0224] MS m / z (ESI): 431.2 [M+H] +

[0225] 1H NMR(400MHz, DMSO-d6)δ8.80(s,1H),8.69(d,J=8.4Hz,1H),7.47(dd,J=8.7,7.2Hz,2H),7.33-7.27(m,3H),7 .04(s,2H),6.63(d,J=1.7Hz,2H),4.24(t,J=8.3Hz,1H),1.18(s,9H),1.12-1.05(m,1H),0.56-0.35(m,4H).

[0226] Example 2: Synthesis of 2-(tert-butyl)-N-((1S,E)-1-cyclopropyl-3-(N,S-dimethylsulfonylimino)allyl)-4-phenoxypyrimidine-5-carboxamide (compound 2)

[0227] Step 1: Synthesis of compound 2b

[0228] Compound 2a (1.0 g, 10.7 mmol) and paraformaldehyde (387 mg, 12.9 mmol) were dissolved in formic acid (10 mL) and stirred at 100 °C until fully reacted. The reaction mixture was concentrated to dryness, diluted with saturated sodium bicarbonate aqueous solution (100 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give compound 2b (252 mg), crude product.

[0229] Step 2: Synthesis of compound 2c

[0230] Compound 2b (100 mg, 933 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Under argon protection, LDA (2 M, 1.0 mL, 2.0 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 0.5 h. Then, diphenyl chlorophosphate (251 mg, 933 μmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C until fully reacted. Saturated ammonium chloride aqueous solution (20 mL) and ethyl acetate (20 mL) were added to the reaction solution. The mixture was separated, and the organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 2c (70 mg).

[0231] Step 3: Synthesis of compound 2e

[0232] HATU (2.6 g, 7.0 mmol) and DIEA (2.4 g, 18.6 mmol) were added to a DMF (15 mL) solution of compound 1j (1.3 g, 4.6 mmol) and compound 2d (hydrochloride, 769 mg, 4.6 mmol). The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into water (60 mL), stirred at room temperature for 0.5 hours, filtered, the filter cake was washed with water, and dried to obtain compound 2e (1.7 g), the crude product.

[0233] Step 4: Synthesis of compound 2f

[0234] Compound 2e (1.0 g, 2.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and under argon protection, DIBAL (1.5 M, 4.0 mL, 6.0 mmol) was added dropwise at -70 °C with stirring until the reaction was complete. A saturated aqueous solution of ammonium chloride (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filtrate was separated into layers. The organic phase was washed with a saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give compound 2f (600 mg).

[0235] Step 5: Synthesis of Compound 2

[0236] Compound 2c (63.4 mg, 187 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium hydride (60% dispersed in mineral oil, 5.0 mg, 124.5 μmol) was added in portions under ice bath conditions. The mixture was stirred at 0 °C for 1 hour. Then, anhydrous tetrahydrofuran (1 mL) of compound 2f (55 mg, 155 μmol) was added dropwise, and the mixture was stirred at 0 °C until fully reacted. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness. Reversed-phase column chromatography (C18 column, acetonitrile / water = 10%–80%) yielded compound 2 (2 mg).

[0237] LC-MS: m / z (ESI): 443.2 [M+H] +

[0238] 1H NMR (400MHz, DMSO-d6) δ8.82(d,J=4.3Hz,1H),8.72(d,J=8.2Hz,1H),7.52-7.43(m,2H),7.34-7.24(m,3H),6.73(dd,J=15.2,5.2Hz,1H),6.54 (ddd,J=15.1,5.1,1.5Hz,1H),4.38-4.22(m,1H),2.94-2.90(m,3H),2. 50(d,J=3.8Hz,3H),1.30-1.21(m,1H),1.18(s,9H),0.60-0.36(m,4H).

[0239] Example 3: Synthesis of N-((1S,E)-1-cyclopropyl-3-(S-methylsulfonylimino)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (compound 3)

[0240] Step 1: Synthesis of compound 3b

[0241] Potassium carbonate (18.8 g, 135 mmol) and compound 1h (8.52 g, 90.5 mmol) were added sequentially to a DMF (100 mL) solution of compound 3a (20 g, 90.5 mmol) at 0 °C. The mixture was stirred at room temperature until fully reacted. Water (400 mL) was added to the reaction solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was washed with a small amount of water. After drying, compound 3b (24.6 g) was obtained.

[0242] MS m / z(ESI): 279.00 [M+H] + .

[0243] Step 2: Synthesis of compound 3d

[0244] Compound 3c (7.96 g, 53.8 mmol), an aqueous solution of potassium carbonate (9.92 g, 71.8 mmol) (4.33 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.31 g, 1.79 mmol) were added sequentially to a solution of compound 3b (10 g, 35.9 mmol) in 1,4-dioxane (80 mL) at room temperature. After purging with nitrogen, the mixture was stirred at 90 °C until fully reacted. The reaction mixture was partially solvent-removed by rotary evaporation, diluted with ethyl acetate (50 mL), and washed with saturated brine (80 mL). The organic phase was separated, evaporated to dryness, and subjected to silica gel column chromatography (EA / PE = 10%) to give compound 3d (4.3 g).

[0245] 1H NMR(400MHz, CDCl3)δ9.04(s,1H),7.39–7.30(m,2H),7.22–7.17(m,1H),7.15–7.09(m,2H),6. 22–6.14(m,1H),5.43–5.37(m,1H),4.36(q,J=7.1Hz,2H),1.95(s,3H),1.34(t,J=7.1Hz,3H).

[0246] Step 3: Synthesis of compound 3e

[0247] Potassium osmium tetroxide dihydrate (21.0 mg, 57 μmol) was added to a mixed solution of compound 3d (5.4 g, 19.0 mmol) in THF (40 mL) and water (10 mL) at room temperature. After stirring for 5 minutes, sodium periodate (10.6 g, 49.0 mmol) was added. The mixture was stirred at room temperature until fully precipitated, and a solid was formed. The reaction solution was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were evaporated to dryness to give compound 3e (5.1 g). The crude product was used directly in the next step.

[0248] MS m / z(ESI): 287.10 [M+H] + .

[0249] Step 4: Synthesis of compound 3f

[0250] Bis(2-methoxyethyl)aminosulfur trifluoride (11.0 g, 49.9 mmol) was added dropwise to a solution of compound 3e (5.1 g, 17.8 mmol) in dichloroethane (50 mL) at room temperature. The mixture was stirred at 80 °C until fully reacted. After the reaction solution was cooled to 0 °C, water (80 mL) was slowly added dropwise to quench the reaction, and the mixture was extracted twice with dichloromethane (50 mL). The combined organic phases were evaporated to dryness and subjected to silica gel column chromatography (EA / PE = 10%) to give compound 3f (4.6 g).

[0251] MS m / z(ESI): 309.00 [M+H] + .

[0252] 1 H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 7.46–7.40 (m, 2H), 7.29 (t, J = 7.4Hz, 1H), 7.21– 7.17(m,2H),4.46(q,J=7.1Hz,2H),1.83(t,J=18.6Hz,3H),1.42(t,J=7.1Hz,3H).

[0253] Step 5: Synthesis of 3g of compound

[0254] At room temperature, an aqueous solution (40 mL) of lithium hydroxide monohydrate (1.66 g, 39.6 mmol) was added dropwise to a THF (40 mL) solution of compound 3f (6.1 g, 19.8 mmol). The mixture was stirred at room temperature until fully reacted. After removing THF from the reaction mixture, 2 M hydrochloric acid aqueous solution (30 mL) was slowly added dropwise, and a solid precipitated. The solid was extracted twice with ethyl acetate (40 mL). The combined organic phases were evaporated to dryness to give compound 3 g (5.4 g). The crude product was used directly in the next step.

[0255] Step Six: Synthesis of Compound 3h

[0256] Compound 2a (1.0 g, 10.7 mmol) was dissolved in anhydrous THF (50 mL). Sodium hydride (644 mg, 16.1 mmol, 60% dispersed in mineral oil) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Di-tert-butyl dicarbonate (3.1 g, 14.0 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature until fully reacted. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was directly purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 3h (274 mg).

[0257] Step 7: Synthesis of Compound 3i

[0258] Compound 3h (100 mg, 517 μmol) was dissolved in anhydrous THF (2 mL) under argon protection. Diisopropylaminolithium (0.5 mL, 2N, 1.1 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Diphenyl chlorophosphate (139 mg, 517 μmol) was then added dropwise, and the mixture was stirred at 0 °C until fully reacted. The reaction solution was poured into water (20 mL), extracted twice with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give compound 3i (74 mg).

[0259] Step 8: Synthesis of Compound 3j

[0260] HATU (338 mg, 889 μmol) and DIEA (310 mg, 2.4 mmol) were added to a DMF (3 mL) solution of compound 3 g (166 mg, 592 μmol) and compound 2d (hydrochloride, 98.1 mg, 592 μmol). The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into water (20 mL), extracted twice with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 3j (130 mg).

[0261] Step Nine: Synthesis of Compound 3k

[0262] Compound 3j (130 mg, 332 μmol) was dissolved in anhydrous THF (2.5 mL) under argon protection. Diisobutylaluminum hydride (0.5 mL, 1.5 N, 764 μmol) was added dropwise at -70 °C, and the mixture was stirred at -70 °C until fully reacted. The reaction solution was poured into a saturated ammonium chloride aqueous solution (10 mL), stirred for 10 min, filtered through diatomaceous earth, and the filter cake was washed with an appropriate amount of ethyl acetate. The filtrate was separated into layers, and the aqueous phase was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 3k (70 mg).

[0263] Step 10: Synthesis of Compound 3l

[0264] Compound 3i (70.6 mg, 166 μmol) was dissolved in anhydrous THF (2 mL). Sodium hydride (4.4 mg, 111 μmol, 60% dispersed in mineral oil) was added dropwise at 0–5 °C. The mixture was stirred at 0 °C for 1 h. Then, anhydrous THF (1 mL) solution of compound 3k (50.0 mg, 138 μmol) was added dropwise, followed by stirring at 0 °C until the reaction was complete. The reaction mixture was poured into water (20 mL), extracted three times with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound 3l (74 mg).

[0265] Step 11: Synthesis of Compound 3

[0266] Compound 3 (60.0 mg, 112 μmol) was dissolved in anhydrous acetonitrile (3 mL), and p-toluenesulfonic acid (23.1 mg, 134 μmol) was added. The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase chromatography (C18 column, acetonitrile / water = 65%–90%) to give compound 3 (12 mg).

[0267] LC-MS: m / z (ESI): 437.2 [M+H] + .

[0268] 1 H NMR(400MHz, DMSO-d6)δ9.00(s,1H),8.96-8.88(m,1H),7.54-7.45(m,2H),7.38-7.28(m,3H),6.90-6.82(m,1H),6.79(dd,J=15.1,4.3Hz,1H ),4.36-4.24(m,1H),2.94-2.88(m,3H),1.87(t,J=19.0Hz,3H),1.17- 1.04(m,1H),0.64-0.53(m,1H),0.53-0.44(m,2H),0.43-0.36(m,1H).

[0269] Example 4: Synthesis of N-((1S,E)-1-cyclopropyl-3-(S-methylsulfonylimino)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide (compound 4)

[0270] Step 1: Synthesis of compound 4b

[0271] Compound 3b (1.25 g, 4.5 mmol) was added to a 50 mL reaction flask, along with 1,4-dioxane (10 mL) and water (1 mL). The mixture was stirred under argon protection. Then, compound 4a (1.0 g, 5.2 mmol), potassium carbonate (1.9 g, 13.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (328 mg, 448 μmol) were added sequentially to the system. The mixture was stirred at 85 °C until fully reacted. The mixture was diluted with ethyl acetate (150 mL), washed twice with water (30 mL × 2), washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was mixed with silica gel for column chromatography purification using gradient elution (0-25% EA / PE). The product was collected to obtain compound 4b (487 mg).

[0272] Step 2: Synthesis of compound 4c

[0273] Compound 4b (480 mg, 1.6 mmol) was added to a 50 mL reaction flask, along with anhydrous THF (9 mL) and water (3 mL). The mixture was stirred, followed by the addition of potassium osmium hydrate (48.3 mg, 131 μmol). The mixture was stirred for 10 min, and then sodium periodate (992 mg, 4.64 mmol) was added. The mixture was stirred at room temperature until fully reacted. The mixture was diluted with ethyl acetate (100 mL), washed twice with water (20 mL × 2), twice with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain compound 4c (480 mg). The crude product was used directly in the next reaction step.

[0274] Step 3: Synthesis of compound 4d

[0275] Compound 4c (480 mg, 1.54 mmol) was added to a 50 mL reaction flask, followed by 2 mL of dichloromethane. The mixture was stirred, and then 3 mL of diethylaminosulfur trifluoride was added. The mixture was stirred at room temperature until fully reacted. The system was cooled in an ice bath, and then the reaction was quenched with 15 mL of saturated sodium bicarbonate solution. Dichloromethane (60 mL) was added, and the mixture was allowed to separate into layers. The organic phase was washed once with 20 mL of water and once with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography with gradient elution (0-40% EA / PE). The product was collected to give compound 4d (330 mg).

[0276] Step 4: Synthesis of compound 4e

[0277] Compound 4d (330 mg, 987 μmol) was added to a 25 mL reaction flask, followed by 6 mL of THF and 3 mL of water. The mixture was stirred, and then lithium hydroxide monohydrate (126 mg, 3.0 mmol) was added. The system was stirred at room temperature until fully reacted. The system was diluted with 10 mL of water, and the pH was adjusted to 2-3. The mixture was then extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give compound 4e (300 mg). The crude product was used directly in the next reaction.

[0278] Step 5: Synthesis of compound 4f

[0279] Compound 4e (390 mg, 1.3 mmol) was added to a 25 mL reaction flask, followed by 10 mL of DMF and stirring. Then, compound 2d (hydrochloride, 232 mg, 1.4 mmol) and HATU (726 mg, 1.9 mmol) were added, and finally DIEA (658 mg, 5.1 mmol) was added. The mixture was stirred at room temperature until fully reacted. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with water (15 mL × 2), washed twice with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was directly purified by silica gel column chromatography (0-50% EA / PE) to give compound 4f (339 mg).

[0280] Step Six: Synthesis of 4g of Compound

[0281] Compound 4f (339 mg, 812 μmol) was added to a 25 mL reaction flask, followed by toluene (9 mL). Diisobutylaluminum hydride (1.5 M, 1.25 mL) was added dropwise at -70 °C. After the addition was complete, the reaction system was stirred at -78 °C until fully induced. The system was quenched with methanol (3 mL) and diluted with ethyl acetate (40 mL). It was then washed twice with 10% potassium sodium tartrate aqueous solution (10 mL × 2), once with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was directly purified by silica gel column chromatography (0-60% EA / PE) to give 4 g (127 mg) of compound.

[0282] Step 7: Synthesis of compound 4h

[0283] Compound 3i (167 mg, 393 μmol) was added to a 25 mL reaction flask, along with 2 mL of anhydrous THF. Under argon protection, sodium hydride (11.8 mg, 295 μmol, 60% dispersed in mineral oil) was added at 0-5 °C, and the reaction mixture was stirred at 0-5 °C for 0.5 h. Compound 4 g (127 mg, 328 μmol) was dissolved in 1 mL of anhydrous THF and added to the above system. The mixture was slowly heated to allow it to react completely. The system was quenched with 10 mL of water, diluted with 40 mL of ethyl acetate, washed once with 10 mL of water, washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give compound 4 h (184 mg). The crude product was used directly in the next reaction step.

[0284] Step 8: Synthesis of Compound 4

[0285] Compound 4h (220 mg, 391 μmol) was added to a 25 mL reaction flask, followed by 3 mL of ACN and stirring. Then, p-toluenesulfonic acid (135 mg, 782 μmol) was added, and the mixture was stirred at room temperature until fully reacted. The mixture was diluted with 50 mL of ethyl acetate, washed once with 15 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase chromatography (C18 column, acetonitrile / water = 40%–75%) to obtain compound 4 (35 mg).

[0286] LC-MS: m / z (ESI): 463.1 [M+H] + .

[0287] 1 H NMR(400MHz, CDCl3)δ9.46(s,1H),7.85-7.74(m,1H),7.50(t,J=7.8Hz,2H),7.37(t,J=7.5Hz,1H),7.30-7.22(m,2H),7.00-6.90(m,1H),6.77-6 .65(m,1H),4.29-4.23(m,1H),3.02(d,J=3.1Hz,3H),2.64(brs,1H),1.5 8-1.46(m,1H),1.13-1.04(m,1H),0.82-0.64(m,4H),0.59-0.41(m,4H).

[0288] Example 5: Synthesis of compounds 3-1 and 3-2

[0289] Compound 3 (70 mg) prepared using the method of Example 3 was separated by chiral separation (CHIRALPAK IC, 10 μm silica, 30 mm diameter, 250 mm length, using a mixture of ethanol (containing 0.1% ammonia) and carbon dioxide to maintain polarity (40%) to obtain compound 3-1 (22.5 mg, first peak, retention time 5.0 min) and compound 3-2 (12.7 mg, second peak, retention time 6.2 min).

[0290] Compound 3-1: MS m / z (ESI): 437.2 [M+H] + ;

[0291] 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.96-8.88(m,1H),7.55-7.43(m,2H),7.39-7.28(m,3H),6.90-6.7 4(m,2H),4.36-4.24(m,1H),2.91(s,3H),1.87(t,J=19.0Hz,3H),1.17-1.05(m,1H),0.62-0.34(m,4H).

[0292] Compound 3-2: MS m / z (ESI): 437.2 [M+H] + ;

[0293] Example 6: Synthesis of compounds 4-1 and 4-2

[0294] Compound 4 (35 mg) obtained in Example 4 was separated by chiral separation (CHIRALPAK IC, 10 μm silica, 30 mm diameter, 250 mm length, using a mixture of ethanol (containing 0.1% ammonia) and carbon dioxide to maintain polarity (15%) to obtain compound 4-1 (6.0 mg, first peak, retention time 3.6 min) and compound 4-2 (6.4 mg, second peak, retention time 4.1 min).

[0295] Compound 4-1: MS m / z (ESI): 463.3 [M+H] + ;

[0296] 1 H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 8.92 (d, J = 8.4Hz, 1H), 7.52-7.44 (m, 2H), 7.39 -7.26(m,3H),6.92-6.68(m,2H),4.34-4.24(m,1H),3.89(s,1H),2.87(s,3H),1.72-1.54(m,1H),1.16-1.02(m,1H),0.65-0.34(m,8H).

[0297] Compound 4-2: MS m / z (ESI): 463.3 [M+H] + ;

[0298] Example 7: Synthesis of N-((1S,E)-1-cyclopropyl-3-(N-cyclopropyl-S-methylsulfonylimino)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (compound 5)

[0299] Step 1: Synthesis of compound 5a

[0300] Compound 1c (600 mg, 3.01 mmol) was dissolved in anhydrous acetonitrile (10 mL), followed by the addition of anhydrous lithium chloride (128 mg, 3.01 mmol), compound 3i (2.57 g, 6.04 mmol), and DIEA (1.95 g, 15.1 mmol). The mixture was stirred at room temperature until fully reacted. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and purified by reversed-phase column chromatography (C18 column, acetonitrile / water = 5%–80%). The purified filtrate was lyophilized to give compound 5a (650 mg).

[0301] Step 2: Synthesis of compound 5b

[0302] Compound 5a (300 mg, 801 μmol) was dissolved in anhydrous dichloromethane (6 mL), and TFA (275 mg, 2.41 mmol) was added. The mixture was stirred at room temperature until fully reacted. The reaction solution was concentrated under reduced pressure and purified by reversed-phase chromatography (C18 column, acetonitrile / water = 25%-60%) to obtain compound 5b (123 mg).

[0303] Step 3: Synthesis of compound 5c

[0304] Compound 5b (20.0 mg, 72.9 μmol) was added to a 2 mL reaction flask, followed by anhydrous toluene (0.3 mL) and water (0.1 mL). Then, copper acetate (2.65 mg, 14.6 μmol), 1,10-phenanthroline (2.63 mg, 14.6 μmol), and potassium carbonate (30.2 mg, 219 μmol) were added. The mixture was stirred for 10 min, and then potassium cyclopropyltrifluoroborate (21.6 mg, 146 μmol) was added. The mixture was stirred at 60 °C until fully reacted. The reaction solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography with gradient elution (0-20% THF / PE). The product was collected to give compound 5c (18 mg).

[0305] Step 4: Synthesis of compound 5d

[0306] Compound 5c (16 mg, 50.9 μmol) was dissolved in 1 mL of anhydrous dichloromethane, and 1 mL of TFA was added. The mixture was stirred thoroughly at room temperature. The reaction solution was concentrated under reduced pressure to obtain crude 5d (trifluoroacetate), which was used directly in the next reaction step.

[0307] Step 5: Synthesis of Compound 5

[0308] Compound 5 (12 mg) was synthesized and purified using compound 5d (trifluoroacetate, 16.7 mg, 50.9 μmol) and compound 3g (14.3 mg, 50.9 μmol) as starting materials, in accordance with the method in step 12 of Example 1.

[0309] LC-MS: m / z (ESI): 477.3 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.96-8.88(m,1H),7.49(t,J=7.9Hz,2H),7.38-7.24(m,3H),6.78(dd,J=15.1,4. 6Hz,1H),6.64(dd,J=15.2,1.6Hz,1H),4.38-4.29(m,1H),2.89(s,3H),2.36-2.27(m,1H),1.87(t,J=19.0Hz,3H),1.32 -1.04(m,2H),0.65-0.31(m,4H),0.26-0.21(m,2H).

[0311] Biological activity and related property test examples

[0312] The compounds in the following test examples were all prepared according to the methods described in the embodiments of this disclosure.

[0313] Test Example 1: Assay of WRN ATP hydrolase inhibitory activity

[0314] Experimental Principle

[0315] WRN unwinding is driven by the hydrolysis of ATP by the ATP-hydrolyzing domain in the WRN protein. ATP hydrolysis generates ADP, releasing energy to promote WRN unwinding. The ADP generated in 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; changes in the signal value reflect changes in the ATP-hydrolyzing activity of the WRN protein.

[0316] Experimental instruments

[0317] Experimental materials

[0318] Experimental methods

[0319] The analyte was dissolved in DMSO, and the stock solution concentration was 10 mM. The stock solution was serially diluted using the Echo instrument's dose-response program with DMSO as the dilution solvent. The total experimental volume was 4 μL, starting at 10 μM, with 3-fold dilutions and 10 concentration points. The total volume of the compound and DMSO was 160 nL, and the final DMSO concentration was 0.4%. 2 μL of 2X WRN-ATP mixture (buffer: 25 mM Tris-HCl (pH 8.0), 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. Then, 2 μL of 2X Hec1 (0.4 nM) was added and incubated at room temperature for 0.5 hours. Next, 4 μL of ADP-Glo ​​reagent (ADP-Glo ​​detection kit) was added and incubated for another 1 hour. Finally, 8 μL of Detection reagent (ADP-Glo ​​detection kit) was added and incubated at room temperature for 1 hour. The chemiluminescence signal values ​​were read on an Envision microscope. 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 wells was calculated. The IC50 was calculated using a four-parameter fitting method based on the inhibition rate. 50 .

[0320] The experimental results are shown in the table below:

[0321] The compounds disclosed in this embodiment exhibit good WRN ATP hydrolase inhibitory activity.

[0322] Test Example 2: HCT-116 Cell Proliferation Experiment

[0323] Experimental Principle

[0324] The HCT-116 cell line used in the experiment was an MSI (microsatellite instability) cell line. The proliferation assay used a kit (…). The 2.0 Luminescent Cell Viability Assay quantifies ATP in living cells and tests the inhibitory effect of compounds on cell proliferation. The kit generates a luminescent signal that is directly proportional to the amount of ATP, which in turn is directly proportional to the number of cells.

[0325] Experimental instruments

[0326] Experimental materials

[0327] Experimental methods

[0328] HCT-116 cells were cultured in McCoy's 5A + 10% FBS. After trypsin digestion, the cell concentration was adjusted to 300 / 40 μL / well in 384-well plates and cultured overnight at 37°C in a 5% CO2 incubator. The test compound was dissolved in DMSO, with a stock solution concentration of 10 mM. The stock solution was serially diluted using the Echo instrument's dose-response program with DMSO as the dilution solvent. The program conditions were: total experimental volume 40 μL, starting at 10 μM, 3-fold dilution, 10 concentration points, and a total volume of 200 nL for both compound and DMSO. After 4 days of incubation, the cell plates were equilibrated to room temperature, and 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. Cell control wells were defined as 0% inhibition controls, and culture medium wells as 100% inhibition controls. The inhibition rate of the sample wells was calculated. The IC50 was calculated using a four-parameter fitting method based on the inhibition rate. 50 .

[0329] The experimental results are shown in the table below:

[0330] The compounds disclosed herein exhibit good anti-cell proliferation activity against microsatellite unstable cells.

[0331] Test Example 3: Detection of In Vitro Metabolic Stability of Rat Hepatocytes

[0332] The concentration of compounds in the reaction system was determined by LC / MS / MS to calculate the intrinsic clearance rate of the test compounds and to assess their in vitro metabolic stability in rat hepatocytes.

[0333] 198 μL 0.5 × 10 6 A mixture of rat hepatocytes / mL and 2.0 μL of the test compound or positive control Verapamil was added to the incubation plate to initiate the reaction. Incubation was performed at 37 °C and 900 rpm. At 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the incubation mixture was transferred to a stop plate (each well containing 150 μL of acetonitrile containing 100 nM alprazolam, 200 nM caffeine, and 100 nM tosylate). The mixture was then vortexed for 5 minutes. The stop plate was centrifuged at 3220 g for 45 minutes. 100 μL of the supernatant from each compound was transferred to a 96-well plate, followed by dilution with 100 μL of purified water.

[0334] The obtained samples were quantified by ion chromatogram. The residual rate was calculated based on the peak area of ​​the analyte or positive control. The slope k was determined using Microsoft Excel by linear regression of the natural logarithm of the residual rate against incubation time.

[0335] Intrinsic clearance rate (in vitro CL) int μL / min / 10 6 The slope value k is calculated from the following equation (for cells):

[0336] in vitro CL int =-kV / N

[0337] V = incubation volume (0.25 mL);

[0338] N = Number of cells per well (0.125 × 10⁻⁶) 6 cell)

[0339] The experimental results are shown in the table below:

[0340] Note: The structural formula of VVD-133214 (RO7589831) is shown below, and it can be prepared according to Example 87 of WO2024010782A1:

[0341] Conclusion: The compound of this embodiment has a lower in vitro rat hepatocyte clearance rate compared to the control molecule.

[0342] Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

[0343] Using Balbc mice as test animals, the plasma drug concentrations at different time points after intravenous injection and gavage administration of the compound of this invention were determined by LC / MS / MS. The pharmacokinetic behavior of the compound of this invention in mice was studied to evaluate its pharmacokinetic characteristics.

[0344] Three healthy male Balbc mice aged 6-8 weeks were used in each group.

[0345] Intravenous administration (IV): Weigh a certain amount of the drug, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of physiological saline to prepare a colorless, clear and transparent liquid at 1 mg / mL.

[0346] Oral administration (PO): Weigh a certain amount of the drug, add 0.5% by mass of hydroxypropyl methylcellulose, 0.1% by volume of Tween 80 and 99.6% by volume of physiological saline to prepare a white suspension of 1 mg / mL.

[0347] Balbc mice were fasted overnight before being administered the drug via intravenous injection or oral gavage.

[0348] The compound of the present invention was administered to mice via tail vein injection at a dose of 2 mg / kg. Blood samples of 0.02 mL were collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The samples were placed in test tubes containing EDTA-K2 and centrifuged at 4000 rpm for 5 minutes at 4°C to separate the plasma. The plasma was then stored at -80°C.

[0349] Alternatively, mice can be administered the compound of the present invention by gavage at a dose of 10 mg / kg. 0.02 mL of blood should be collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood should be placed in a test tube containing EDTA-K2, centrifuged at 4000 rpm for 5 minutes at 4°C to separate the plasma, and stored at -80°C.

[0350] To determine the content of the analyte compound in mouse plasma after gavage administration of different drug concentrations: 10 μL of mouse plasma was collected at each time point after administration, and 150 μL (50 ng / mL) of dexamethasone acetonitrile solution (internal standard) was added. The mixture was vortexed for 30 seconds, centrifuged at 12000 rpm for 15 minutes at 4°C, and the supernatant was diluted three times with water. 2.0 μL of the supernatant was then analyzed by LC-MS / MS. AB SCIEX was used. 1.7.3. Run and manage the LC-MS / MS liquid chromatography-mass spectrometry system and collect data. Calculate pharmacokinetic parameters using the non-compartmental model statistical moment method with Phoenix WinNonlin 8.0 software.

[0351] The experimental results are shown in the table below:

[0352] Conclusion: Compared with the control molecule, the compounds of this disclosure exhibited lower apparent clearance and longer half-life in mice when administered intravenously, and greater exposure when administered orally by gavage.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, X 3 Selected from O, NH or NR 5 ; When X 3 When selected from O, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 4-6 membered heterocyclic group or C1-C6 alkyl group, wherein the 4-6 membered heterocyclic group is optionally R 10a The C1-C6 alkyl group is replaced by R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace; When X 3 Selected from NH or NR 5 At that time, R 11 It is hydrogen, R 10 Selected from NR 8 R 9 C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or, the R 10 R 5 Together with the atoms bonded to it, they form 4-10 membered heterocyclic groups, wherein the 4-10 membered heterocyclic groups are optionally subjected to R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 11a replace; R 10a R 11a Each is independently selected from halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 8 R 9 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C(O)C1-C6 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or C(O)C1-C6 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally subjected to R 9a replace; R 8a R 9a Each is independently selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy or C1-C6 alkyl; R 5 Selected from cyano, C(=O)C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C(=O)C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 5a replace; R 5a Selected from halogen, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy; L 2 Selected from -C(=O)NH-, -C(=S)NH-, -S(=O)2NH-, 1,2,3-triazolyl, oxadiazolyl, imidazolyl, tetrazolyl, pyrazolyl, -NHC(=O)NH-, -NHC(=O)O-, -CH(CF3)NH- or R 3 Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 5-12 membered heterocyclic groups, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 5-12 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are selectively coated with R. 3a replace; R 3a Selected from halogen, cyano, hydroxy, amino, carboxyl, oxo, -S-C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -S-C1-C6 alkyl, -O-C3-C6 cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2 or phenoxy, wherein the amino, -S-C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -S-C1-C6 alkyl, -O-C3-C6 cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2 or phenoxy is optionally R 3b replace; R 3b Selected from halogens or C1-C6 alkyl groups; L 1 Selected from bonds, O, S, NH, CH2, or OCH2; R 1 Selected from hydrogen, C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group are optionally replaced by R 1a replace; R 1a Selected from halogen, deuterium, cyano, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, oxo, -S-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl or carboxyl; X is selected from N or CR x ; Y is selected from N or CR y ; Z is selected from N or CR. z ; Alternatively, Y and Z, along with their linked bonds, form a 5-10 quinary heterocyclic ring or a 5-12 quinary heterocyclic ring, which is optionally composed of R. 7 replace; The condition is that X, Y, and Z are not all N at the same time; R 7 Selected from halogens, cyano groups, amino groups, NHC(=O)C1-C6 alkyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, NH(C1-C6 alkyl groups), N(C1-C6 alkyl)2, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups; or two R groups attached to adjacent ring atoms. 7 Together with the atoms they are attached to, they form C5-C. 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 membered heterocyclic rings or 5-10 membered heteroaromatic rings, wherein C5-C 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 quinary heterocyclic rings, or 5-10 quinary heterocyclic rings can be selected by R. 7a replace; R 7a Selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R x R y and R z Each is independently selected from H, halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 haloalkyl or C3-C6 cycloalkyl; R 2 Selected from halogens, cyano groups, NHC(=O)C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, wherein the C3-C8 cycloalkyl, C5-C 10 Cycloalkenyl, C6-C 10 Aryl, C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, C1-C6 alkoxy, -O-C3-C8 cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, optionally with R 2a Replace; or R 2 Y and the carbon atoms they are attached to form C6-C. 10 Aromatic rings, C5-C 10 Cyclic olefin rings, 5-10 membered heteroaromatic rings, or 5-12 membered heterocycles, wherein the C6-C 10 Aromatic rings, C5-C 10 Cycloolefin rings, 5-10 membered heteroaromatic rings, or 5-12 membered heterocycles may be selectively replaced by R. 6 replace; R 2a Selected from hydroxyl, oxo, halogen, C1-C6 alkyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, amino, carboxyl, -S-C1-C6 alkyl, -S-C3-C8 cycloalkyl, or -O-C3-C8 cycloalkyl, wherein the C1-C6 alkyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, -S-C1-C6 alkyl, -S-C3-C8 cycloalkyl, or -O-C3-C8 cycloalkyl is optionally R 2b replace; R 2b Selected from halogens or C1-C6 alkyl groups; R 6 Selected from halogens, cyano groups, amino groups, NHC(=O)C1-C6 alkyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, NH(C1-C6 alkyl groups), N(C1-C6 alkyl)2, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups; or two R groups attached to adjacent ring atoms. 6 Together with the atoms they are attached to, they form C5-C. 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 membered heterocyclic rings or 5-10 membered heteroaromatic rings, wherein C5-C 10 Cyclic olefin ring, C6-C 10 Aromatic rings, 4-12 quinary heterocyclic rings, or 5-10 quinary heterocyclic rings can be selected by R. 6a replace; R 6a It is selected from halogen, cyano, amino, NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, yes 3. The compound of formula (I) according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from C1-C6 alkyl, 4-6 membered heterocyclic or NR 8 R 9 The C1-C3 alkyl group is R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form 4-6 member heterocyclic groups; or Among them, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from C1-C3 alkyl, 4-membered heterocyclic or NR 8 R 9 The C1-C3 alkyl group is R 10a Replace; or, R 10 R 11 Together with the atoms bonded to it, they form a 4-membered heterocyclic group; or Among them, X 3 Selected from O, R 11 It is hydrogen, R 10 Selected from methyl, aziridine, oxetidine or NR 8 R 9 The methyl group is R 10a The substituted nitrogen-containing heterocyclic butyl group or oxocyclic butyl group is optionally replaced by R. 10a Replace; or, R 10 R 11 Together with the atoms connected to it, they form 4. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, R 10a Selected from C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; or, R 10a Selected from C3-C4 cycloalkyl groups; or R 10a Selected from cyclopropyl.

5. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, R 8 R 9 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or C(O)C1-C3 alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, or C(O)C1-C3 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally subjected to R 9a Replace; or Among them, R 8 R 9 Each is independently selected from hydrogen, C1-C3 alkyl, cyclopentyl, or C(O)C1-C3 alkyl, wherein the C1-C3 alkyl, cyclopentyl, or C(O)C1-C3 alkyl is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a 4-membered heterocyclic group, which is optionally R 9a Replace; or Among them, R 8 R 9 Each is independently selected from hydrogen, methyl, ethyl, cyclopentyl, or C(O)CH3, wherein the methyl, ethyl, cyclopentyl, or C(O)CH3 is optionally R 8a Replace; or R 8 R 9 Together with the nitrogen atom attached thereto, they form a nitrogen-containing heterocyclic butyl group, wherein the nitrogen-containing heterocyclic butyl group is optionally R 9a replace; and / or R 8a Selected from C1-C6 alkoxy groups; or, R 8a Selected from C1-C3 alkoxy groups; or R 8a Selected from methoxy groups.

6. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, Selected from 7. The compound of formula (I) according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 10a Replace; or, the R 10 R 5 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 10a Replace; or Among them, X 3 Selected from NH or NR 5 ;R 10 Selected from C1-C3 alkyl groups; or, the R 10 R 5 Together with the atoms bonded to it, they form a 6-membered heterocyclic group; or Among them, X 3 Selected from NH or NR 5 ;R 10 Selected from methyl, or R 10 R 5 Together with the atoms connected to it, they form or Among them, X 3 Selected from NH, R 10 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally R 10a Replace; or Among them, X 3 Selected from NH, R 10 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 10a Replace; or Among them, X 3 Selected from NH, R 10 Selected from C1-C3 alkyl groups.

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, R 5 Selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally R 5a Replace; or, the R 5 R 10 Together with the atoms bonded to it, they form a 4-6 membered heterocyclic group, which is optionally R 10a Replace; or Among them, R 5 Selected from C1-C3 alkyl or C3-C4 cycloalkyl, or R 5 R 10 Together with the atoms bonded to it, they form a 6-membered heterocyclic group; or Among them, R 5 Selected from methyl or cyclopropyl, or R 5 R 10 Together with the atoms connected to it, they form 9. The compound of formula (I) according to any one of claims 7-8, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, Selected from or, Selected from 10. The compound of formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, L 2 Selected from -C(=O)NH-, -C(=S)NH-, -S(=O)2NH-, -NHC(=O)NH-, -NHC(=O)O- or -CH(CF3)NH-; or, L 2 Selected from -C(=O)NH- or -C(=O)N(C1-C3 alkyl)-; or, L 2 Selected from -C(=O)NH-.

11. The compound of formula (I) according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, R 3 Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 5-6 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 5-6 membered heterocyclic group is optionally R 3a Replace; or, R 3 Selected from C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl group is optionally R 3a Replace; or, R 3 Selected from cyclopropyl.

12. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, L 1 Selected from key or O; or, L 1 It is O.

13. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, R 1 Selected from C3-C8 cycloalkyl, C6-C 10 aryl or 5-6-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C 10 Aryl or 5-6 quinone heteroaryl groups are selectively substituted with R. 1a Replace; or, R 1 Selected from C6-C 10 Aryl; or, R 1 Selected from phenyl.

14. The compound of formula (I) according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, X is selected from N or CR x Y is selected from N or CR y Z is selected from N or CR z The condition is that X, Y, and Z are not simultaneously N; or, X is selected from N, Y is selected from N, and Z is selected from CR. z ; and / or R z Selected from H, halogen, amino, C1-C6 alkyl or NHC(=O)C1-C6 alkyl; or, R z Selected from H.

15. The compound of formula (I) according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, R 2 Selected from C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C3-C8 cycloalkyl), N(C1-C6 alkyl)(C3-C8 cycloalkyl), C2-C6 alkenyl, -S-C1-C6 alkyl, or C1-C6 alkoxy is optionally R 2a Replace; or, R 2 Selected from C1-C6 alkyl, amino, -S-C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl, amino, -S-C1-C6 alkyl, or C1-C6 alkoxy is optionally R 2a Replace; or R 2 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally R 2a Replace; or, R 2 Selected from C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally R 2a Replace; or R 2 Selected from methyl, ethyl, or tert-butyl, wherein the methyl, ethyl, or tert-butyl group is optionally R 2a replace; and / or R 2a Selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino, carboxyl, or -S-C1-C6 alkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, amino, or -S-C1-C6 alkyl is optionally R 2b Replace; or, R 2a Selected from halogens or C3-C4 cycloalkyl groups; or R 2a Selected from fluorine or cyclopropyl.

16. The compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: Among them, R 10 X 3 R 3 L 2 L 1 R 1 R 2 X, Y, and Z are as defined in any one of claims 1-15.

17. The compound of formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: Among them, R 10 R 11 X 3 R 3 L 2 L 1 R 1 R 2 X, Y, and Z are as defined in any one of claims 1-15.

18. The compound of formula (I) according to any one of claims 1-2, 7-15, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: Among them, R 10 R 11 R 3 L 2 L 1 R 1 R 2 X, Y and Z are as defined in any one of claims 1-2 and 7-15.

19. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, The compound of formula (I) is selected from the following compounds:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

21. Use of the compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition of claim 20, in the preparation of a medicament for inhibiting WRN.

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