Ring-fused compound and application thereof

Abstract

The invention provides a fused ring compound shown in a formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, a pharmaceutical composition containing the fused ring compound or the pharmaceutically acceptable salts or the stereoisomers thereof, and application of the fused ring compound as a WRN inhibitor in prevention or treatment of related diseases.

Description

[0001] Cross-references 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. 202410606966.3, filed May 16, 2024; Chinese Patent Application No. 202411383222.6, filed September 30, 2024; and Chinese Patent Application No. 202510071098.8, filed January 16, 2025. The entire contents of the above patent applications are incorporated herein by reference. Technical Field

[0003] This disclosure relates to cyclic 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 most representative RecQ helicases, WRN includes an exonuclease domain in addition to the helicase domain. Werner syndrome (WS) is an autosomal recessive disorder that presents with symptoms of accelerated clinical aging, leading to a mean life expectancy of less than 50 years. WS helicase / RecQ-like 1 (WRN) is involved in many important pathways, including DNA replication, recombination and repair. WRN can unwind non-canonical secondary DNA structures that can be encountered during replication and recombination processes, and its mutation can cause chromosomal instability diseases such as Werner syndrome. Normally, WRN depletion leads to DNA double-strand breaks in MSI cells, resulting in cell cycle arrest and / or apoptosis. Studies have shown that there is a strong synthetic lethal relationship between WRN helicase and microsatellite instability-high (MSI-H) cancer. WRN forms a synthetic lethal relationship with MutL homolog 1 (MLH1), and MLH1 loss is associated with microsatellite instability (MSI).

[0007] Microsatellites are simple repeat sequences of less than 10 nucleotides in the genome, and DNA mismatch repair (MMR) defects caused by gene mutations or promoter hypermethylation can cause hypermutation of nucleotide repeat regions (microsatellites), i.e. microsatellite instability (MSI). MSI can promote the occurrence of various cancers, including colon cancer (15%), gastric cancer (22%), endometrial cancer (20-30%) and ovarian cancer (12%), of which 45-60% do not respond to immune checkpoint blockade. Therefore, MSI-type tumors need new treatment methods. In two whole-genome gene inactivation studies using CRISPR or RNA interference, WRN was identified as the most essential dependency of MSI-H cells, and this dependency is related to the helicase activity, but not to the nuclease function of WRN. These findings, combined with the good tolerance of microsatellite stable (MSS) cancer cells to WRN silencing, demonstrate that WRN is a potential specific target for treating MSI tumors.

[0008] In view of the huge unmet clinical needs, the development of small molecule inhibitors targeting WRN has broad application prospects. SUMMARY

[0009] The present disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0010]

[0011] wherein ring A is selected from 5-6 membered heteroaryl or phenyl, which is optionally substituted;

[0012] R 7 is selected from hydrogen, halogen, cyano, amino, NHC(=O)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl or C3-C6cycloalkyl, X 2 is selected from O, S, CH2or NH, X 1 , L 1 and the atoms to which they are attached form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring or a C5-C6cycloalkenyl ring, which is optionally substituted;

[0013] or, R 7 , X 2 and the atoms to which they are attached form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a C5-C6cycloalkenyl ring or a phenyl ring, which is optionally substituted, X 1 is selected from O or NH, L 1 is selected from a bond, O, S, NR, CH2or OCH2, which CH2or OCH2is optionally substituted with halogen, R is selected from hydrogen, C1-C3alkyl or C1-C3haloalkyl;

[0014] Q is selected from Q 1 , Q 2 , Q 3 or Q 4 ;

[0015] Q 1 is wherein, represents is in the (Z) configuration or in the (E) configuration;

[0016] X 3 is selected from O, NH or NR 5 ;

[0017] R 4 is selected from C1-C6alkyl, C3-C6cycloalkyl or 4-6 membered heterocyclyl, which C1-C6alkyl, C3-C6cycloalkyl or 4-6 membered heterocyclyl is optionally substituted;

[0018] R 5 is selected from cyano, C(=O)C1-C6alkyl, C1-C6alkyl, C3-C6cycloalkyl or 4-6 membered heterocyclyl, which C(=O)C1-C6alkyl, C1-C6alkyl, C3-C6cycloalkyl or 4-6 membered heterocyclyl is optionally substituted;

[0019] Q 2 is wherein, representative is in the (Z) configuration or the (E) configuration;

[0020] Q 3 is

[0021] Q 4 is wherein R a is C1-C6 alkyl, optionally substituted;

[0022] R 1 is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 alkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, optionally substituted; 10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, optionally substituted;

[0023] n is selected from 1, 2, or 3;

[0024] R 2 is 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, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted; 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, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted; or R 2 and the atom to which they are attached to form a 4-12 membered heterocyclic ring or a C4-C8 cycloalkene ring, optionally substituted;

[0025] R 3 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, optionally substituted;10 Aryl or 5-10 membered heteroaryl optionally substituted.

[0026] In some embodiments, ring A is selected from 5-6 membered heteroaryl or phenyl, optionally substituted with R A substituted; R A selected from halogen, cyano, amino, NHC(=O)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl, or C3-C6cycloalkyl.

[0027] In some embodiments, ring A is selected from 6 membered heteroaryl or phenyl, optionally substituted with R A substituted.

[0028] In some embodiments, ring A is selected from pyrimidinyl, phenyl, pyrazolyl, pyrrolyl, pyridinyl, triazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl, optionally substituted with R A substituted.

[0029] In some embodiments, ring A is selected from pyrimidinyl or phenyl.

[0030] In some embodiments, ring A is selected from pyrimidinyl.

[0031] In some embodiments, selected from

[0032] In some embodiments, selected from

[0033] In some embodiments, selected from

[0034] In some embodiments, R 7 selected from hydrogen, halogen, cyano, amino, NHC(=O)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl, or C3-C6cycloalkyl, X 2 selected from O or S, X 1 , L 1 and the atoms connecting them together form a 5-6 membered heteroaromatic ring, 5-6 membered heterocyclic ring, or C5-C6cycloalkenyl ring, optionally substituted.

[0035] In some embodiments, R7 selected from hydrogen, halogen, cyano, amino, NHC(=0)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl, or C3-C6cycloalkyl, X 2 is selected from O or S, X 1 , L 1 and the atoms connected thereto form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, or a C5-C6cycloalkene ring, which is optionally substituted with R 8 substituted, R 8 is selected from halogen, cyano, hydroxy, C1-C6alkyl, or C1-C6alkoxy.

[0036] In some embodiments, R 7 is selected from hydrogen, X 2 is selected from O, X 1 , L 1 and the atoms connected thereto form a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, which is optionally substituted with R 8 substituted.

[0037] In some embodiments, R 7 is selected from hydrogen, X 2 is selected from O, X 1 , L 1 and the atoms connected thereto form a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring.

[0038] In some embodiments, R 7 is selected from hydrogen, X 2 is selected from O, X 1 , L 1 and the atoms connected thereto form wherein a represents the bond shared with ring A, and * represents the atom connected to R 1 .

[0039] In some embodiments, R 7 is selected from hydrogen, X 2 is selected from O, X 1 , L 1 and the atoms connected thereto form wherein a represents the bond shared with ring A, and * represents the atom connected to R 1 .

[0040] In some embodiments, R 7 , X 2and the atoms connected thereto form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a C5-C6 cycloalkene ring or a phenyl ring, which is optionally substituted with R 9 substituted, R 9 is selected from halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 alkoxy, X 1 is selected from O or NH, L 1 is selected from a bond, O, S, NR, CH2or OCH2, which CH2or OCH2is optionally substituted with halogen; R is selected from hydrogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0041] In some embodiments, R 7 , X 2 and the atoms connected thereto form a 5-6 membered heteroaromatic ring or a phenyl ring, which is optionally substituted with R 9 substituted, X 1 is selected from O or NH, L 1 is selected from O.

[0042] In some embodiments, R 7 , X 2 and the atoms connected thereto form a 5-6 membered heteroaromatic ring or a phenyl ring, X 1 is selected from O or NH, L 1 is selected from O.

[0043] In some embodiments, R 7 , X 2 and the atoms connected thereto form

[0044] the is optionally substituted with R 8 substituted, X 1 is selected from O or NH, L 1 is selected from O; wherein a represents the bond common to ring A and X 1 and the atoms connected thereto.

[0045] In some embodiments, R 7 , X 2 and the atoms connected thereto form X 1 is selected from O or NH, L 1 is selected from O; wherein a represents the bond common to ring A and X 1 and the atoms connected thereto.

[0046] In some embodiments, R 8It is selected from halogens, C1-C6 alkyl groups, or C1-C6 alkoxy groups.

[0047] In some implementation schemes, R 8 Selected from C1-C3 alkyl groups.

[0048] In some implementation schemes, R 8 Selected from methyl.

[0049] In some implementations, Q is selected from Q 1 Q 1 yes in, represent It is either (Z) configuration or (E) configuration.

[0050] In some implementation schemes, Q 1 yes

[0051] In some implementation schemes, X 3 Selected from O or NH.

[0052] In some implementation schemes, X 3 Selected from O.

[0053] In some implementation schemes, R 4 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 4a Replace, where R 4a It is selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl or C1-C6 alkoxy.

[0054] In some implementation schemes, R 4 Selected from C1-C6 alkyl or 4-6 membered heterocyclic groups.

[0055] In some implementation schemes, R 4 Selected from C1-C3 alkyl groups.

[0056] In some implementation schemes, R 4 Selected from methyl.

[0057] In some implementation schemes, 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 It is selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl or C1-C6 alkoxy.

[0058] In some implementations, Q is selected from...

[0059] In some implementations, Q is selected from...

[0060] In some implementation schemes, R 1 Selected from C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclic, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclic group may be optionally substituted. In some embodiments, R 1 Selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 alkyl, C6-C 10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic, wherein the C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 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 It is 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.

[0061] In some implementation schemes, R 1 Selected from 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 It is 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.

[0062] In some implementation schemes, R 1 Selected from C3-C8 cycloalkyl, C6-C 10 aryl or 5-6 heteroaryl, wherein the C3-C8 cycloalkyl, C6-C 10 Aryl or 5-6 quinone heteroaryl groups are selectively coated with R. 1a replace.

[0063] In some implementation schemes, R 1 Selected from C6-C 10C6-C10aryl or C3-C8cycloalkenyl, which C6-C10aryl or C3-C8cycloalkenyl is optionally substituted with R 10 C6-C10aryl or C3-C8cycloalkenyl, which C6-C10aryl or C3-C8cycloalkenyl is optionally substituted with R 1a substituted.

[0064] In some embodiments, R 1 is selected from C6-C10aryl or C3-C8cycloalkenyl. 10 aryl.

[0065] In some embodiments, R 1 is selected from C6-C10aryl or C3-C8cycloalkenyl.

[0066] In some embodiments, R 1 is selected from C6-C10aryl.

[0067] In some embodiments, R 1 is selected from C6-C10aryl or C3-C8cycloalkenyl. 10 aryl, C3-C8cycloalkyl or C3-C8cycloalkenyl, which C6-C10aryl or C3-C8cycloalkenyl is optionally substituted with R 10 aryl, C3-C8cycloalkyl or C3-C8cycloalkenyl, which C6-C10aryl or C3-C8cycloalkenyl is optionally substituted with R 1a substituted.

[0068] In some embodiments, R 1 is selected from C6-C10aryl, C3-C8cycloalkyl or C3-C8cycloalkenyl.

[0069] In some embodiments, R 1 is selected from C6-C10aryl, C3-C8cycloalkyl or C3-C8cycloalkenyl.

[0070] In some embodiments, n is selected from 1 or 2.

[0071] In some embodiments, n is selected from 1.

[0072] In some embodiments, R 2 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl. 10 cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl. 10 cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl. 10 cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl. 10C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R

[0073] In some embodiments, R 2 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 10 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 10 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 10 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 10 is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 2a is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R

[0074] R 2a is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R

[0075] In some embodiments, R 2a is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 2b is selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with R 2bhalogen or C1-C6alkyl.

[0076] In some embodiments, R 2 C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, or C1-C6alkoxy, said C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, or C1-C6alkoxy being optionally substituted with R 2a substituted.

[0077] In some embodiments, R 2 C1-C4alkyl, said C1-C4alkyl being optionally substituted with R 2a substituted.

[0078] In some embodiments, R 2 methyl, ethyl, or tert-butyl, said methyl, ethyl, or tert-butyl being optionally substituted with R 2a substituted.

[0079] In some embodiments, R 2a hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, cyano, amino, or -S-C1-C6alkyl, said C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, amino, or -S-C1-C6alkyl being optionally substituted with R 2b substituted.

[0080] In some embodiments, R 2a halogen or C3-C4cycloalkyl.

[0081] In some embodiments, R 2a F or cyclopropyl.

[0082] In some embodiments, R 2 tert-butyl,

[0083] In some embodiments, n is selected from 2.

[0084] In some embodiments, R 2 with the atom to which they are attached form a 4-12 membered heterocyclic ring or a C4-C8cycloalkene ring, said 4-12 membered heterocyclic ring or C4-C8cycloalkene ring being optionally substituted with R 2a substituted.

[0085] R 2 together with the atom to which they are attached form a 4-10 membered heterocyclic ring or a C5-C6cycloalkene ring, which is optionally substituted with R 2a .

[0086] R 2 together with the atom to which they are attached form a 4-10 membered heterocyclic ring.

[0087] R 2 together with the atom to which they are attached form a 6 membered heterocyclic ring.

[0088] R 2 together with the atom to which they are attached form wherein b represents a conjugated pi bond shared with ring A.

[0089] R 3 is selected from C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, which C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with R 3a ; R 3a is selected from halogen, cyano, hydroxyl, amino, carboxyl, oxo, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy, which amino, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy is optionally substituted.

[0090] R 3aselected from halogen, cyano, hydroxy, amino, carboxy, oxo, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy, said amino, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy being optionally substituted by R 3b substituted; R 3b is selected from halogen or C1-C6alkyl.

[0091] In some embodiments, R 3 is selected from C3-C6cycloalkyl or 4-10 membered heterocyclyl, said C3-C6cycloalkyl or 4-10 membered heterocyclyl being optionally substituted by R 3a substituted.

[0092] In some embodiments, R 3 is selected from C3-C4cycloalkyl or 4 membered heterocyclyl, said C3-C4cycloalkyl or 4 membered heterocyclyl being optionally substituted by R 3a substituted.

[0093] In some embodiments, R 3 is selected from cyclopropyl, cyclobutyl, or oxetanyl, said cyclopropyl, cyclobutyl, or oxetanyl being optionally substituted by R 3a substituted.

[0094] In some embodiments, R 3a is selected from halogen, amino, C1-C6alkyl, C1-C6alkoxy, -S-C1-C6alkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), or C(=O)N(C1-C6alkyl)2, said amino, C1-C6alkyl, C1-C6alkoxy, -S-C1-C6alkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), or C(=O)N(C1-C6alkyl)2 being optionally substituted by R 3b substituted.

[0095] In some embodiments, R 3a is selected from halogen.

[0096] In some embodiments, R 3 is selected from cyclopropyl, oxetanyl, or

[0097] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing, of the present disclosure is selected from a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing:

[0098]

[0099] wherein L 1 , R 1 , R 2 , R 3 , R 7 , X 1 , X 2 , Q and ring A are as defined above.

[0100] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing, of the present disclosure is selected from a compound of Formula (III), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing:

[0101]

[0102] wherein n, L 1 , R 1 , R 2 , R 3 , R 7 , X 1 , X 2 , Q and ring A are as defined above.

[0103] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing, of the present disclosure is selected from a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a stereoisomer of the foregoing:

[0104]

[0105] wherein represents a single or double bond, R 1 , R 2 , R 3 , R 7 and Q are as defined above.

[0106] In some embodiments, the compound of Formula (I) of the present disclosure is selected from the following compounds:

[0107]

[0108]

[0109]

[0110]

[0111] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a pharmaceutically acceptable excipient.

[0112] In another aspect, the present disclosure provides a method of inhibiting WRN comprising the step of contacting WRN with a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof.

[0113] In another aspect, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof for use as a WRN inhibitor.

[0114] In another aspect, the present disclosure provides a method of treating a disease mediated by WRN helicase in a mammal comprising administering to a mammal, preferably a human, in need of such treatment, 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.

[0115] In another aspect, the present 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 for the manufacture of a medicament for the prevention or treatment of a disease mediated by WRN helicase.

[0116] In another aspect, the present 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 for the prevention or treatment of a disease mediated by WRN helicase.

[0117] In another aspect, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition thereof for the prevention or treatment of a disease mediated by WRN helicase.

[0118] In some embodiments, the disease mediated by WRN helicase is a disease in which WRN helicase is inhibited.

[0119] In some embodiments, the disease mediated by WRN helicase is selected from cancer or Werner syndrome.

[0120] Definitions and explanations of terms

[0121] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, the definitions of groups and terms recited in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other arbitrarily. A specific term should not be considered as indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0122] Herein represents a connection site.

[0123] Herein represents the N atom in the connecting group as a connection site.

[0124] Unless otherwise indicated, a wedge-shaped bond and a dashed wedge-shaped bond and represent the absolute configuration of a stereocenter.

[0125] Herein represents the (Z) configuration or the (E) configuration, for example represents the (Z) configuration or the (E) configuration

[0126]

[0127] Herein The double bond on ring A represents a conjugated π-bond on a 5-6 membered heteroaryl or phenyl group, in specific molecules of the present application, some molecules represent the π-bond as a double bond, for example Some molecules represent the π-bond as a single bond, for example

[0128] Herein When R 7 , X 2 and the atoms connected thereto together form a 5-6 membered heteroaromatic ring or a benzene ring, the double bond between X 2 and the carbon atom represents a conjugated π-bond on a 5-6 membered heteroaromatic ring or a benzene ring, in specific molecules of the present application, some molecules represent the π-bond as a double bond, for example

[0129] Some molecules represent the π-bond as a single bond, for example

[0130] The term "tautomer" refers to isomers of a functional group that result from the movement of a certain atom in a molecule to two positions. The compounds of the present disclosure can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0131] The term "stereoisomers" refers to isomers that have the same molecular formula but different physical structures. The physical properties of stereoisomers are different. The term "geometric isomers" refers to stereoisomers that have the same molecular formula and sequence of atoms but differ in the spatial arrangement of atoms. The term "enantiomers" refers to pairs of non-superimposable mirror images of molecules that have the same molecular formula and sequence of atoms but have one or more chiral centers of the same configuration. The term "diastereomers" refers to stereoisomers that have the same molecular formula and sequence of atoms but differ in the spatial arrangement of atoms.

[0132] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric form can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain an enantiomeric or diastereomeric excess, all of which are within the scope of the present disclosure. Additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms or asymmetric double bonds can be present in a substituent such as an alkyl group, and all such isomers are included within the scope of the present disclosure. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically active or racemic forms. This

[0133] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, provided that the valence of the designated atom is not exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced.

[0134] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), multi-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not chemically possible.

[0135] When any variable (e.g. R a ) occurs more than one time in a compound; its definition in each occurrence is independent of its definition at every other occurrence. For example, if a group is substituted with 2 R b groups, then each R b group is selected independently. b

[0136] When one of the variables is selected from a bond or nothing, it means that the two groups to which it is attached are directly connected, such as L represents a bond in A-L-Z means that the structure is actually A-Z.

[0137] When a linking group referred to herein is not indicated as to its direction of attachment, its direction of attachment is arbitrary. For example, when L 1 in structural unit is selected from "C1-C3 alkylene-O", then L 1 may either connect ring Q and R 1 to form "ring Q-C1-C3 alkylene-O-R 1 " in the left-to-right direction or connect ring Q and R 1 to form "ring Q-O-C1-C3 alkylene-R 1 " in the right-to-left direction.

[0138] When a bond of a substituent crosses over to two atoms of a ring, the substituent can be bonded to either atom of the ring. For example, structural unit indicates that R 5 can be substituted at any position on the phenyl ring.

[0139] C m -C n herein means an integer number of carbon atoms in the range of m to n. For example, "C1-C 10 ​"" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0140] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The 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".

[0141] The term "halogenated alkyl" refers to a group formed by replacing one or more hydrogen atoms on an alkyl group with a halogen, including monohalogenated or polyhalogenated alkyl groups, specific examples of which include, but are not limited to, trifluoromethyl, 2,2,2-trichloroethyl, or 3-fluoropropyl.

[0142] 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 "Ci-C6alkoxy" can be understood as "Ci-C6alkyloxy" or "Ci-C6alkyl-O-". The "Ci-C6alkoxy" can further comprise "Ci-C3alkoxy". 10 "alkoxy" can comprise "Ci-C6alkoxy" and "Ci-C3alkoxy" and the like, the "Ci-C6alkoxy" can further comprise "Ci-C3alkoxy".

[0143] The term "alkenyl" refers to straight-chain or branched-chain unsaturated aliphatic hydrocarbon groups consisting of carbon and hydrogen atoms and having at least one double bond. The term "C2-Ci0alkenyl" can be understood as meaning a straight-chain or branched-chain unsaturated hydrocarbon group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms which contains one or more double bonds and which is optionally substituted by one or more radicals selected from the group consisting of "halogen", "hydroxyl", "C1-C4alkyl", "C1-C4haloalkyl", "C1-C4alkoxy", "C1-C4haloalkoxy", "C3-C6cycloalkyl", "C3-C6halocycloalkyl", "C1-C4alkyl-O-". 10 "alkenyl" can be understood as meaning a straight-chain or branched-chain unsaturated hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-Ci0alkenyl", preferably "C2-C6alkenyl", further preferably "C2-C4alkenyl", more preferably C2or C3alkenyl. It is to be understood that, in the case where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, isopropenyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl or (Z)-l-methylprop-l-enyl and the like. 10 "alkenyl" can be understood as meaning a straight-chain or branched-chain unsaturated hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-Ci0alkenyl", preferably "C2-C6alkenyl", further preferably "C2-C4alkenyl", more preferably C2or C3alkenyl. It is to be understood that, in the case where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, isopropenyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl or (Z)-l-methylprop-l-enyl and the like.

[0144] The term "cycloalkyl" refers to a carbocyclic ring which is fully saturated and which exists in the form of a monocyclic, fused, bridged or spirocyclic ring and the like. Unless indicated otherwise, the carbocyclic ring is generally a 3- to 10-membered ring. The term "C3-Ci0cycloalkyl" can be understood as meaning a saturated monocyclic, fused, spirocyclic or bridged cyclic ring which has 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Particular examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl and the like. The term "C3-C6cycloalkyl" can be understood as meaning a saturated monocyclic, fused, spirocyclic or bridged cyclic ring which has 3, 4, 5 or 6 carbon atoms, particular examples including, but not being limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like. The term "C3-C4cycloalkyl" can be understood as meaning a saturated monocyclic, fused, spirocyclic or bridged cyclic ring which has 3 or 4 carbon atoms. The term "C4-C6cycloalkyl" can be understood as meaning a saturated monocyclic, fused, spirocyclic or bridged cyclic ring which has 4, 5 or 6 carbon atoms. 10 "alkenyl" can be understood as meaning a straight-chain or branched-chain unsaturated hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-Ci0alkenyl", preferably "C2-C6alkenyl", further preferably "C2-C4alkenyl", more preferably C2or C3alkenyl. It is to be understood that, in the case where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, isopropenyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl or (Z)-l-methylprop-l-enyl and the like. 10 "alkenyl" can be understood as meaning a straight-chain or branched-chain unsaturated hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-Ci0alkenyl", preferably "C2-C6alkenyl", further preferably "C2-C4alkenyl", more preferably C2or C3alkenyl. It is to be understood that, in the case where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, isopropenyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl or (Z)-l-methylprop-l-enyl and the like.

[0145] 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".

[0146] The term "heterocyclyl" refers to a monocyclic, bicyclic, spiro, or bridged ring radical which is completely saturated or partially saturated, having from 1 to 5 heteroatoms or heteroatom groups (i.e., an atom group containing a heteroatom) in the ring atoms, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, and the like, in the ring atoms. The term "4-18 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and having from 1 to 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. The term "4-12 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and having from 1 to 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. "4-10 membered heterocyclyl" includes "4-7 membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; and specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclyl can also be a bicyclic radical, wherein specific examples of 5,5 membered bicyclic radical include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radical include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl can be a benzo-fused or heteroaromatic annulated radical of the aforementioned 4-7 membered heterocyclyl, including, but not limited to, dihydroisoquinolinyl, and the like. The heterocyclyl can also be a tricyclic radical. "4-10 membered heterocyclyl" can include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", and the like. "4-7 membered heterocyclyl" can further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", and the like.In the present disclosure, although some bicyclic heterocyclyl moieties contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl is still overall non-aromatic.

[0147] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring system having a conjugated pi-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 aryl" is to be understood as aryl having 6 to 20 carbon atoms. In particular a ring having 6 carbon atoms ("C6-aryl"), such as, for example, a phenyl group; or a ring having 9 carbon atoms ("C9-aryl"), such as, for example, an indane or indenyl group; or a ring having 10 carbon atoms ("C 10 aryl"), such as, for example, a tetrahydronaphthyl, dihydronaphthyl or naphthyl group; or a ring having 13 carbon atoms ("C 13 aryl"), such as, for example, a fluorenyl group; or a ring having 14 carbon atoms ("C 14 aryl"), such as, for example, an anthryl group. The term "C6-C 10 aryl" is to be understood as aryl having 6 to 10 carbon atoms. In particular a ring having 6 carbon atoms ("C6-aryl"), such as, for example, a phenyl group; or a ring having 9 carbon atoms ("C9-aryl"), such as, for example, an indane or indenyl group; or a ring having 10 carbon atoms ("C 10 aryl"), such as, for example, a tetrahydronaphthyl, dihydronaphthyl or naphthyl group.

[0148] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromaticity, wherein at least one ring atom is selected from N, O, S, the remaining ring atoms being C. The term "5-10 membered heteroaryl" is to be understood as including monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and the like and their benzo derivatives, such as quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl or phenoxazinyl and the like. "5-10 membered heteroaryl" includes "5-6 membered heteroaryl". The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0149] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom through a substitution reaction, such as a nucleophilic displacement reaction. For example, representative leaving groups include, but are not limited to, triflate, chloro, bromo, iodo, sulfonate (e.g., methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate) or acyloxy (e.g., acetoxy, trifluoroacetoxy) and the like.

[0150] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0151] The term "hydroxy" refers to the -OH group.

[0152] The term "amino" refers to the -NH2 group.

[0153] 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 Werner Syndrome RecQ DNA helicase. The term "WRN" includes mutants, fragments, variants, isoforms and homologs of full-length wild-type WRN. "Diseases or conditions mediated by WRN" include diseases or conditions that are treated by WRN inhibition, such as cancer.

[0154] The term "therapeutically effective amount" means an amount of a compound of the disclosure that (i) treats a particular disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner.

[0155] The term "pharmaceutically acceptable" with respect to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0156] The term "pharmaceutically acceptable salt" refers to salts of a pharmaceutically acceptable acid or base, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

[0157] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0158] The term "pharmaceutically acceptable excipient" refers to those excipients which do not cause significant irritation to an organism and do not have untoward effects of the

[0159] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this document, can be understood to encompass the terms "consisting of" or "consisting of".

[0160] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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.

[0161] Certain isotopically-labeled compounds of the present disclosure (for example, those into which radioactive isotopes such as3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution analyses. Tritiated (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 are useful in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can be prepared by introducing an isotopically-labeled reagent in place of the non-labeled reagent used in the schemes and / or examples disclosed herein.

[0162] The pharmaceutical compositions of the disclosure can be prepared by combining a compound of the disclosure with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, creams, lotions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0163] Typical routes of administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0164] The pharmaceutical compositions of the disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, emulsifying, re- freezing drying, or lyophilizing processes.

[0165] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compound with a pharmaceutically acceptable excipient well known in the art. These excipients enable the compounds of the disclosure to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0166] Solid oral compositions can be prepared by conventional mixing or compounding equipment using conventional coating methods. For example, the active compound can be mixed with a solid excipient, optionally ground using a suitable mill, and if necessary, processed through a sieve and / or filler. Suitable excipients include, but are not limited to, binders, diluents, disintegrating agents, lubricants, glidants, or flavoring agents.

[0167] The pharmaceutical compositions can also be in unit dosage form in ampules or disposable syringes or in multi-dose containers, for easy of of administration and uniformity of dosage.

[0168] In all methods of administration of the compounds of general formula I described herein, the daily dose can range from 0.01 mg / kg to 100 mg / kg of body weight, in single or divided doses.

[0169] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0170] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples described below, all substituents unless otherwise indicated are as previously defined. The chemical reactions described in the schemes and examples are performed in any suitable order unless otherwise indicated. Sometimes it is necessary to protect certain functionalities. These protections are removed at a convenient stage to give the desired compound. Sometimes it is necessary to choose a protecting group for a particular functionality. The choice of protecting group is well known in the art, for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in the present disclosure are incorporated herein in their entirety.

[0171] One important consideration in the planning of synthetic routes in the art is the choice of 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 the present disclosure are incorporated herein in their entirety.

[0172] The following abbreviations are used in the present disclosure:

[0173] DETAILED DESCRIPTION

[0174] The present disclosure is described in detail by the following examples, but it is not meant to limit the present disclosure in any way. The present disclosure has been described in detail by specific embodiments, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0175] Unless otherwise indicated, ratios indicated for mixed solvents are by volume.

[0176] Compounds are named by hand or by software. Compounds are named by hand or by software.

[0177] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half maximal inhibitory concentration, which refers to the concentration at which the maximum inhibitory effect is halved.

[0178] The eluent below can be formed into a mixed eluent by two or more solvents, and the ratio is the volume ratio of each solvent.

[0179] Example 1, synthesis of (E)-2-(tert-butyl)-6-(1-(3,3-difluorocyclobutyl)-3- (methylsulfonyl)allyl)-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one (Compound 1)

[0180]

[0181]

[0182] Step one: synthesis of compound 1b

[0183] Compound 1a (10.0 g, 82 mmol) was dissolved in THF (15 mL). Dess-Martin reagent (45.21 g, 106.6 mmol) was added under ice bath. The resulting mixture was stirred at room temperature for sufficient reaction. Filtration was performed, and the filter cake was washed with a small amount of dichloromethane. The filtrate was washed with saturated sodium thiosulfate (10 mL) twice, and then washed with saturated sodium bicarbonate solution (10 mL) three times. Concentration was performed, and the crude product was purified by flash column chromatography (DCM / PE = 0%-50%) to obtain compound 1b (3.2 g).

[0184] Step two: synthesis of compound 1d

[0185] Compound 1b (3.2 g, 26.7 mmol) was dissolved in DCM (30 mL). Then compound 1c (5.5 g, 45 mmol) and titanium tetraisopropoxide (9.1 g, 32 mmol) were added. The resulting mixture was stirred at room temperature for sufficient reaction. Concentration was performed, and the crude product was purified by flash column chromatography (EA / PE = 0%-30%) to obtain compound 1d (1.8 g).

[0186] Step three: synthesis of compound 1f

[0187] Compound 1d (1.8 g, 8.1 mmol) was dissolved in DCM (25 mL). The solution was cooled to -60 °C, and then compound 1e (1 M in THF, 9 mL) was added slowly dropwise. After the addition was complete, the resulting reaction solution was allowed to warm to room temperature and react fully. After quenching with water (30 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The crude product was purified by flash column chromatography (EA / PE = 10% to 45%) to give compound 1f (1.6 g).

[0188] Step Four: Synthesis of Compound 1g

[0189] Compound 1f (100 mg) was dissolved in a solution of hydrochloric acid in dioxane (4 M, 3 mL), and the mixture was stirred at room temperature to react fully. The volatiles were removed under vacuum to give compound 1g (58 mg, hydrochloride salt).

[0190] Step Five: Synthesis of Compound 1j

[0191] Compound 1h (500 mg, 2.5 mmol) and 1i (hydrochloride salt, 340 mg, 2.5 mmol) were added to anhydrous ethanol (5 mL), and the mixture was stirred at 80 °C to react fully. The reaction solution was rotary evaporated and purified by flash column chromatography (PE:EA = 5:1) to give compound 1j (422 mg).

[0192] Step Six: Synthesis of Compound 1k

[0193] Compound 1j (422 mg, 1.9 mmol) was added to a solution of Bredereck reagent (3 mL), and the mixture was stirred at 120 °C to react fully. The reaction solution was purified by flash reverse-phase column chromatography (acetonitrile:water = 5:95 to 70:30) to give compound 1k (360 mg).

[0194] Step Seven: Synthesis of Compound 1l

[0195] Compound 1k (150 mg, 541 μmol) and 1g (hydrochloride salt, 99 mg, 541 μmol) were added to anhydrous ethanol (2 mL), and the mixture was stirred at 80 °C to react fully. The reaction solution was purified by reverse-phase column chromatography (acetonitrile:water = 5:95 to 70:30) to give compound 1l (101 mg).

[0196] Step Eight: Synthesis of Compound 1m

[0197] Compound 1 1 (100 mg, 0.3 mmol) was dissolved in THF (4 mL) and water (1 mL) was added. Then potassium osmate dihydrate (24.8 mg, 0.067 mmol) and sodium periodate (173 mg, 0.8 mmol) were added. The mixture was reacted thoroughly at room temperature. Diluted with EA (10 mL) and washed with saturated sodium thiosulfate solution (10 mL) and then washed twice with saturated brine (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and purified by flash column chromatography (PE:EA = 3:1) to give compound 1 m (76 mg).

[0198] Step nine: synthesis of compound 1 n

[0199] Compound 1 m (76 mg, 227 μmol) and p-toluenesulfonic acid monohydrate (1.6 mg, 8.5 μmol) were added to ethylene glycol (1 mL) and the mixture was reacted thoroughly at 120 °C. The reaction solution was purified by reverse column chromatography (acetonitrile:water = 5:95~70:30) to give compound 1 n (85.0 mg).

[0200] Step ten: synthesis of compound 1 o

[0201] Compound 1 n (85 mg, 224 μmol) was added to DMF (1 mL) and then NBS (40 mg, 224 μmol) was added at 0 °C. The mixture was reacted thoroughly at room temperature. The reaction solution was purified by flash column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 1 o (66 mg).

[0202] Step eleven: synthesis of compound 1 p

[0203] Compound 1 o (66 mg, 144 μmol), phenylboronic acid (19.7 mg, 161 μmol), potassium phosphate (45 mg, 214 μmol) and Pd(dppf)Cl2(7.8 mg, 10.7 μmol) were added to dioxane (1 mL) and water (0.2 mL) and then reacted thoroughly at 100 °C. The reaction solution was purified by flash column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 1 p (54 mg).

[0204] Step twelve: synthesis of compound 1 q

[0205] Compound 1p (46 mg, 100 mΐΐ) was added to dioxane (0.5 mL), then hydrochloric acid aqueous solution (6 N, 0.5 mL) was added and then reacted thoroughly at 50 °C. Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (2 mL x 3), the organic phase was combined and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to give compound 1q (33 mg) which was purified by flash column chromatography (petroleum ether: ethyl acetate = 3: 1).

[0206] Step thirteen: synthesis of compound 1

[0207] Compound 1q (33 mg, 80 mΐΐ), compound 1r (23 mg, 100 mΐΐ), lithium chloride (3.4 mg, 80 mΐΐ) and DIPEA (31 mg, 242 mΐΐ) were added to anhydrous THF (0.5 mL) and reacted thoroughly at room temperature. Compound 1 (15 mg) was directly purified by flash reverse phase column chromatography (acetonitrile: water = 5:95 ~ 80:20).

[0208] MS m / z (ESI): 488.3 [M+H] + .

[0209] 1 H NMR (400 MHz, DMSO-d6) d 9.54 (s, 1H), 8.08 (s, 1H), 7.81 - 7.68 (m, 2H), 7.48 (td, J = 7.2, 6.3, 1.4 Hz, 2H), 7.42 - 7.33 (m, 1H), 7.02 - 6.89 (m, 2H), 5.70 (dd, J = 11.2, 4.5 Hz, 1H), 3.18 (t, J = 8.5 Hz, 1H), 3.02 (s, 3H), 2.93 - 2.53 (m, 2H), 2.41 - 2.23 (m, 1H), 1.37 (s, 9H).

[0210] Example 2, synthesis of (S,E)-2-(tert-butyl)-8-(cyclohex-1-en-1-yl)-6-(1- cyclopropyl-3-(methylsulfonyl)allyl)pyrido[4,3-d]pyrimidin-5(6H)-one (compound 2)

[0211]

[0212]

[0213] Step one: synthesis of compound 2b

[0214] Compound 2a (21.5 g, 99.9 mmol) was dissolved in THF (100 mL) under argon protection, and stirred in an ice bath at 0-5 °C. Then a solution of red aluminum (350 mmol) in toluene (100 mL) was added dropwise to the above system, and the dropping speed was controlled. The dropping was completed in 20 min. The reaction was stirred at 0-5 °C for sufficient time. Methanol (20 mL) was added to quench the reaction, and sodium potassium tartrate (40 mL, 1 g / mL) was added. The system was stirred for 15 min, and then separated into two layers. The aqueous phase was extracted twice with ethyl acetate (60 mL x 2). The combined organic phase was washed once with saturated sodium bicarbonate aqueous solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give compound 2b (20.1 g).

[0215] Step two: synthesis of compound 2c

[0216] Compound 2b (1.0 g, 5.0 mmol) was dissolved in ethyl acetate (5 mL), and stirred in an ice bath at 0-5 °C. Then a solution of hydrogen chloride in ethyl acetate (3.7 mL, 4 M) was added dropwise to the above system, and stirred at 0-5 °C for 30 min, and then at room temperature for sufficient time. The system was directly concentrated under reduced pressure to dryness to give compound 2c (hydrochloride, 0.5 g). It was directly used in the next reaction.

[0217] Step three: synthesis of compound 2d

[0218] To a solution of compound Ik (574 mg, 2.07 mmol) in ethanol (5 mL) were added DIEA (284 mg, 2.2 mmol) and compound 2c (hydrochloride, 206 mg, 1.5 mmol) successively, and the system was heated at 80 °C for sufficient time. The reaction solution was directly concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (EA / PE = 0-50%) to give compound 2d (181 mg).

[0219] Step four: synthesis of compound 2e

[0220] To a solution of compound 2d (181 mg, 630 μmol) in DMF (2 mL) was added N-bromosuccinimide (135 mg, 756 μmol), and the system was stirred at room temperature for sufficient time. The reaction solution was diluted with ethyl acetate (60 mL), washed twice with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (EA / PE = 0-45%) to give compound 2e (230 mg).

[0221] Step five: synthesis of compound 2g

[0222] To a solution of compound 2e (100 mg, 273 μmol) in 1,4-dioxane (2 mL) was added compound 2f (68.8 mg, 546 μmol), Pd(amphos)Cl2(19.4 mg, 27.3 μmol) and potassium carbonate (94.3 mg, 683 μmol) under nitrogen protection. The mixture was heated at 90 °C and stirred until the reaction was completed. The reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (EA / PE = 0-35%) to obtain compound 2g (93.0 mg).

[0223] Step six: synthesis of compound 2h

[0224] To a solution of compound 2g (90.0 mg, 245 μmol) in dichloromethane (3 mL) was added sodium bicarbonate (82.3 mg, 980 μmol) and Dess-Martin reagent (260 mg, 612 μmol) under ice-bath condition. The mixture was stirred at room temperature until the reaction was completed. The reaction solution was diluted with dichloromethane (60 mL) and washed with 5% aqueous sodium bicarbonate solution (15 mL x 3) and saturated brine (15 mL) for three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to obtain compound 2h (89.0 mg). The crude product was directly used in the next reaction.

[0225] Step seven: synthesis of compound 2

[0226] To a solution of compound Ir (84.1 mg, 365 μmol) in THF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 14.6 mg, 365 μmol) under ice-bath condition. After the mixture was stirred for 5 min, compound 2h (89.0 mg, 244 μmol) was added. The mixture was stirred at room temperature until the reaction was completed. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL x 3) for three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel preparative plate (EA / PE = 1 / 4) to obtain compound 2 (10.0 mg).

[0227] LC-MS: m / z (ESI): 442.2 [M+H] + .

[0228] 1H NMR (400 MHz, CDC13) δ 9.52 (s, 1H), 7.32 (s, 1H), 6.99 (dd, J = 15.2, 4.4 Hz, 1H), 6.45 (dd, J = 15.2, 1.9 Hz, 1H), 5.84-5.81 (m, 1H), 4.96-4.89 (m, 1H), 2.89 (s, 3H), 2.61-2.41 (m, 2H), 2.19-2.12 (m, 2H), 1.76-1.62 (m, 4H), 1.39 (s, 9H), 1.32-1.26 (m, 1H), 0.91-0.82 (m, 1H), 0.65-0.54 (m, 2H), 0.45-0.37 (m, 1H). Example 3, Synthesis of 2-(tert-butyl)-6-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (Compound 3)

[0229]

[0230] Step one: synthesis of compound 3b

[0231] Bis(triphenylphosphine)palladium dichloride (5.8 mg, 8.2 μmol) and potassium carbonate (34.0 mg, 246 μmol) were added to a solution of compound 2e (30.0 mg, 81.9 μmol) and compound 3a (20.0 mg, 164 μmol) in 1,4-dioxane (1 mL) under nitrogen protection, the mixture was heated and stirred at 90 °C for sufficient time. The system was quenched with saturated aqueous sodium chloride solution (10 mL), extracted with ethyl acetate (15 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (EA / PE = 0-40%) to obtain compound 3b (29.0 mg).

[0232] Step two: synthesis of compound 3c

[0233] Palladium on carbon (14.4 mg) and glacial acetic acid (0.5 mL) were added to a solution of compound 3b (49.0 mg, 135 μmol) in methanol (3 mL), the mixture was stirred at room temperature for sufficient time. The reaction solution was filtered through diatomite, and the filtrate was directly concentrated under reduced pressure to dryness to obtain compound 3c (48.0 mg). The crude product was directly used in the next step reaction.

[0234] Step three: synthesis of compound 3d

[0235] Sodium bicarbonate (66.2 mg, 788 μmol) and Dess-Martin periodinane (112 mg, 263 μmol) were added successively to a solution of compound 3c (48.0 mg, 131.3 μmol) in dichloromethane (2 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution and saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (15 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 3d (31.0 mg). The crude product was used directly in the next step.

[0236] Step four: synthesis of compound 3

[0237] Lithium chloride (3.7 mg, 86.7 μmol) and DIEA (33.6 mg, 260 μmol) were added to a solution of compound 3d (31.5 mg, 86.7 μmol) and compound Ir (23.9 mg, 104 μmol) in THF (1 mL). The mixture was stirred at room temperature for 2 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18 column, acetonitrile / water = 30%-50%) to give compound 3 (5.5 mg).

[0238] MS m / z (ESI): 440.1 [M+H] + .

[0239] 1 H NMR (400 MHz, DMSO-d6) δ 7.62-7.53 (m, 3H), 7.37-7.29 (m, 2H), 7.27-7.20 (m, 1H), 6.97 (dd, J = 15.3, 5.3 Hz, 1H), 6.78 (dd, J = 15.3, 1.5 Hz, 1H), 4.70-4.59 (m, 1H), 4.28 (s, 2H), 3.04 (s, 3H), 1.74-1.62 (m, 1H), 1.26-1.22 (m, 1H), 1.11 (s, 9H), 0.77-0.68 (m, 1H), 0.61-0.46 (m, 2H), 0.38-0.23 (m, 1H).

[0240] Example 4, synthesis of (S,E)-2-(tert-butyl)-8-cyclohexyl-6-(1-cyclopropyl-3- (methylsulfonyl)allyl)pyrido[4,3-d]pyrimidin-5(6H)-one (compound 4)

[0241]

[0242] Step one: synthesis of compound 4a

[0243] To a solution of compound 2g (130 mg, 354 μmol) in THF (2 mL) was added 5% palladium-carbon (150 mg), and hydrogen was replaced for three times. The reaction was stirred at room temperature for 2 hours. The reaction was filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (EA / PE = 0-60%) to give compound 4a (52.0 mg).

[0244] Step two: synthesis of compound 4b

[0245] To a solution of compound 4a (15.0 mg, 40.6 μmol) in dichloromethane (1 mL) was added sodium bicarbonate (8.6 mg, 102 μmol) and Dess-Martin reagent (34.4 mg, 81.2 μmol) successively at ice-bath temperature. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane (30 mL), and washed with 5% sodium bicarbonate aqueous solution (10 mL x 2) twice, and saturated brine (10 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give compound 4b (14.0 mg). The crude product was used directly in the next step.

[0246] Step three: synthesis of compound 4

[0247] To a solution of compound 4b (14.0 mg, 38.1 μmol) in THF (1 mL) was added compound Ir (10.5 mg, 45.7 μmol), DIEA (14.8 mg, 114 μmol) and lithium chloride (1.6 mg, 38.1 μmol) successively at ice-bath temperature. The reaction was stirred at room temperature for 2 hours. To the reaction was added water (10 mL), and the organic phase was extracted with ethyl acetate (15 mL x 2) twice. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel preparative plate (EA / PE = 1 / 4) to give compound 4 (8.0 mg).

[0248] LC-MS: m / z (ESI): 444.2 [M+H] + .

[0249] 1H NMR (400 MHz, CDC13) δ 9.52 (s, 1H), 7.21-7.20 (m, 1H), 6.98 (dd, J = 15.3, 4.4 Hz, 1H), 6.41 (dd, J = 15.2, 1.9 Hz, 1H), 4.97-4.90 (m, 1H), 3.17-3.09 (m, 1H), 2.88 (s, 3H), 1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.78-1.71 (m, 1H), 1.41 (s, 9H), 1.29-1.21 (m, 4H), 0.90-0.84 (m, 1H), 0.84-0.74 (m, 2H), 0.64-0.52 (m, 2H), 0.44-0.37 (m, 1H).

[0250] Biological activity and related property test examples

[0251] The compounds in the following test examples were prepared according to the methods of the above examples of the present disclosure.

[0252] Test Example 1: WRN ATP hydrolysis enzyme inhibitory activity assay

[0253] Principle of experiment

[0254] WRN helicase is driven by ATP hydrolysis in the ATP hydrolysis enzyme domain of the WRN protein. ATP hydrolysis generates ADP, releasing energy to promote WRN helicase. The ADP generated in the reaction is detected by the ADP-Glo assay kit (Promega). After adding the detection reagent, the signal value is positively correlated with the amount of ADP generated in the reaction system, and the change in signal value reflects the change in WRN protein ATP hydrolysis enzyme activity.

[0255] Experimental instruments

[0256] Instrument name Equipment manufacturer Model Nanoliter acoustic transfer system Labcyte Echo 650 Microplate reader PerkinElmer Envision 2105

[0257] Experimental materials

[0258]

[0259]

[0260] Experimental method

[0261] The test compound was dissolved in DMSO, and the stock solution was stored at a concentration of 10 mM. The compound stock solution was diluted by the dose-response program of the Echo instrument, and the dilution solvent was DMSO. The total system of the dilution program experiment was 4 μL, the initial concentration was 10 μM, 3-fold dilution, 10 concentration points, and the total volume of the compound and DMSO was 160 nL. The final concentration of DMSO 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. Then, 4 μL of ADP-Glo reagent (ADP-Glo Assay Kit) was added, and incubated for 1 hour. Then, 8 μL of Detection reagent (ADP-Glo Assay Kit) was added, and incubated at room temperature for 1 hour. The chemiluminescence signal value was read on the Envision. The signal value of the WRN reaction well was defined as 0% inhibition control, and the signal value of the well without WRN was defined as 100% inhibition control. The inhibition rate of the compound treatment well was calculated. The inhibition rate was used to calculate the IC50by four-parameter fitting 50 .

[0262] The experimental results are shown in the following table:

[0263]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, ring A is selected from 5-6 membered heteroaryl or phenyl, which is optionally substituted; R 7 selected from hydrogen, halogen, cyano, amino, NHC(=O)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl or C3-C6cycloalkyl, X 2 is selected from O, S, CH2or NH, X 1 , L 1 and the atoms connecting them form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring or a C5-C6cycloalkene ring, which is optionally substituted; or R 7 , X 2 and the atoms bound thereto form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a C5-C6cycloalkene ring or a benzene ring, which is optionally substituted, X 1 is selected from O or NH, L 1 is selected from a bond, O, S, NR, CH2or OCH2, which CH2or OCH2is optionally substituted by halogen, R is selected from hydrogen, C1-C3alkyl or C1-C3haloalkyl; Q is selected from Q 1 , Q 2 , Q 3 or Q 4 ; Q 1 is wherein, represents is in the (Z) configuration or in the (E) configuration; X 3 selected from O, NH or NR 5 ; R 4 selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted; R 5 selected from cyano, C(=O)C1-C6alkyl, C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C(=O)C1-C6alkyl, C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl being optionally substituted; Q 2 is wherein, represents is in the (Z) configuration or in the (E) configuration; Q 3 is Q 4 is wherein R a is C1-C6 alkyl, optionally substituted; R 1 C3-C8cycloalkyl, C3-C8cycloalkenyl, C1-C6alkyl, C6-C10aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, wherein said C3-C8cycloalkyl, C3-C8cycloalkenyl, C1-C6alkyl, C6-C10aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 Rbgroups; 10 C3-C8cycloalkyl, C3-C8cycloalkenyl, C1-C6alkyl, C6-C 10 C3-C8cycloalkyl, C3-C8cycloalkenyl, C1-C6alkyl, C6-C10aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, wherein said C3-C8 n is selected from 1, 2 or 3; 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, 4-12 membered heterocyclic or 5-10 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, 4-12 membered heterocyclic or 5-10 membered heteroaryl, may be optionally substituted; or R on two adjacent ring atoms. 2 Together with the atoms to which it is attached, it forms a 4-12 membered heterocycle or a C4-C8 cyclic olefin ring, wherein the 4-12 membered heterocycle or C4-C8 cyclic olefin ring may optionally be substituted; R 3 selected from C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl is optionally substituted with 1-3 Rfgroups; 10 selected from C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C10aryl, or 5-10 2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, Ring A is selected from a 5-6 membered heteroaryl or phenyl, optionally substituted with R A substituents; R A selected from halogen, cyano, amino, NHC(=0)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl or C3-C6cycloalkyl; or Ring A is selected from a 6-membered heteroaryl or phenyl, which is optionally substituted with R A substituents; or Ring A is selected from pyrimidinyl, phenyl, pyrazolyl, pyrrolyl, pyridinyl, triazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl, optionally substituted with R A substituents; or selected from 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, R 7 selected from hydrogen, halogen, cyano, amino, NHC(=0)C1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, NH(C1-C6alkyl), N(C1-C6alkyl)2, C1-C6haloalkyl or C3-C6cycloalkyl, X 2 selected from O or S, X 1 , L 1 and the atoms connecting them form a 5-6 membered heteroaromatic, 5-6 membered heterocyclic or C5-C6cycloalkenyl ring, which is optionally substituted by R 8 substituted, R 8 selected from halogen, cyano, hydroxy, C1-C6alkyl or C1-C6alkoxy; or R 7 selected from hydrogen, X 2 selected from O, X 1 , L 1 and the atoms linking them form a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, which is optionally substituted with R 8 ; or R 7 selected from hydrogen, X 2 selected from O, X 1 , L 1 and the atoms to which they are attached form a 5-6 membered heteroaromatic or 5-6 membered heterocyclic ring; or R 7 is selected from hydrogen, X 2 is selected from O, X 1 , L 1 and the atoms linking them together form wherein a represents the bond common with ring A and * represents the atom to which R 1 is attached; or R 7 , X 2 and the atom to which they are attached together form a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a C5-C6cycloalkenyl ring or a phenyl ring, which is optionally substituted by R 9 , R 9 is selected from halogen, cyano, hydroxy, C1-C6alkyl or C1-C6alkoxy, X 1 is selected from O or NH, L 1 is selected from a bond, O, S, NR, CH2or OCH2, which CH2or OCH2is optionally substituted by halogen; R is selected from hydrogen, C1-C3alkyl or C1-C3haloalkyl; or R 7 X 2 and the atom to which they are attached form a 5-6 membered heteroaromatic ring or a benzene ring, which is optionally substituted with R 9 X 1 is selected from O or NH, L 1 is selected from O; or R 7 , X 2 and the atoms bound thereto form a 5-6 membered heteroaromatic ring or a benzene ring, X 1 is selected from O or NH, L 1 is selected from O; or R 7 , X 2 and the atom to which they are attached together form said optionally substituted with R 8 , X 1 is selected from O or NH, L 1 is selected from O; wherein a represents the bond common to ring A, and # represents the atom to which X 1 is attached; and / or R 8 selected from halogen, C1-C6alkyl or C1-C6alkoxy; or R 8 selected from C1-C3alkyl.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Q is selected from the group consisting of 1 Q is 1 is in the (Z) configuration or in the (E) configuration; or wherein, represents is in the (Z) configuration or in the (E) configuration; or Q 1 is and / or X 3 selected from O or NH; and / or R 4 selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with R 4a selected from halogen, cyano, hydroxy, amino, C1-C6alkyl, or C1-C6alkoxy; or 4a selected from halogen, cyano, hydroxy, amino, C1-C6alkyl, or C1-C6alkoxy; or R 4 selected from C1-C6alkyl or 4-6 membered heterocyclyl; or R 4 selected from the group consisting of C1-C3alkyl; or R 4 selected from methyl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, R 1 Selected from 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; or R 1 Selected from C6-C 10 aryl, C3-C8 cycloalkyl or C3-C8 cycloalkenyl, wherein the C6-C 10 Aryl, C3-C8 cycloalkyl or C3-C8 cycloalkenyl are optionally R 1a Replace; or R 1 is selected from phenyl, cyclohexyl, or cyclohexenyl.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein n is 1, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. is selected from 1; and / or R 2 C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 10 C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 10 C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 10 C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 10 C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 2a C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, C1-C6alkoxy, -O-C3-C8cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with R 2a C3-C8cycloalkyl, C5-C7cycloalkenyl, C6-C10aryl, C1-C6alkyl R 2 selected from C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, or C1-C6alkoxy, said C1-C6alkyl, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH(C3-C8cycloalkyl), N(C1-C6alkyl)(C3-C8cycloalkyl), C2-C6alkenyl, -S-C1-C6alkyl, or C1-C6alkoxy being optionally substituted with R 2a ; or R 2 selected from C1-C4alkyl, said C1-C4alkyl being optionally substituted with R 2a substituted; and / or R 2a selected from hydroxy, oxo, halogen, C1-C6alkyl, phenyl, C1-C6alkoxy, C3-C6cycloalkyl, cyano, amino, carboxy, -S-C1-C6alkyl, -S-C3-C8cycloalkyl, or -O-C3-C8cycloalkyl, said C1-C6alkyl, phenyl, C1-C6alkoxy, C3-C6cycloalkyl, amino, -S-C1-C6alkyl, -S-C3-C8cycloalkyl, or -O-C3-C8cycloalkyl optionally substituted with R 2b ; R 2b is selected from halogen or C1-C6alkyl; or R 2a selected from hydroxy, halogen, C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, cyano, amino or -S-C1-C6-alkyl, said C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, amino or -S-C1-C6-alkyl being optionally substituted with R 2b or R 2a selected from halogen or C3-C4cycloalkyl.

7. The compound of formula (I) according to any one of claims 1 to 5, wherein n is selected from 2; and / or R on two adjacent ring atoms 2 together with the atom to which they are attached form a 4-12 membered heterocyclic ring or a C4-C8 cycloalkene ring, which is optionally substituted with R 2a ; or R on two adjacent ring atoms 2 together with the atom to which they are attached form a 4-10 membered heterocyclic ring or a C5-C6cycloalkene ring, which is optionally substituted with R 2a ; or R on two adjacent ring atoms 2 with the atom to which it is attached forms a 6-membered heterocyclic ring.

8. The compound of formula (I) according to any one of claims 1 to 7, wherein R 3 selected from C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl, said C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl being optionally substituted with R 10 10 selected from C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocyclyl, C6-C 3a 3a selected from halogen, cyano, hydroxyl, amino, carboxyl, oxo, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy, said amino, -S-C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, -S-C1-C6alkyl, -O-C3-C6cycloalkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)2, or phenoxy being optionally substituted; or​​ R 3 selected from C3-C6cycloalkyl or 4-10 membered heterocyclyl, said C3-C6cycloalkyl or 4-10 membered heterocyclyl optionally substituted with R 3a substituents; or R 3 selected from C3-C4cycloalkyl or 4-membered heterocyclyl, said C3-C4cycloalkyl or 4-membered heterocyclyl being optionally substituted with R 3a substituents; or R 3 selected from cyclopropyl, cyclobutyl, or oxetanyl, said cyclopropyl, cyclobutyl, or oxetanyl being optionally substituted with R 3a substituents; and / or R 3a selected from halogen, amino, C1-C6alkyl, C1-C6alkoxy, -S-C1-C6alkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), or C(=O)N(C1-C6alkyl)2, said amino, C1-C6alkyl, C1-C6alkoxy, -S-C1-C6alkyl, C(=O)NH2, C(=O)NH(C1-C6alkyl), or C(=O)N(C1-C6alkyl)2being optionally substituted by R 3b or R 3a selected from halogen.

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

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a pharmaceutically acceptable adjuvant.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or of a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the prevention or treatment of a WRN helicase mediated disease.

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