Aromatic ring derivatives, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of aromatic ring derivatives, its preparation method and the pharmaceutical composition containing the derivative in medicine.The specific aromatic ring derivative of formula (I) is described in the present application, its preparation method and its pharmaceutically acceptable salt, and their purposes as therapeutic agent, especially as WRN inhibitor;The definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

Technical Field

[0001] This invention relates to an aromatic ring derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a WRN inhibitor. Background Technology

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

[0003] Synthetic lethality refers to the phenomenon where cell death occurs when two non-lethal genes are simultaneously suppressed (suppression can take the form of gene mutations, gene silencing, or other gene defects and / or gene expression knockout, drug inhibition, or other molecular perturbations). This mechanism can be used to identify a specific mutation in cancer, find its "synthetic lethal partner," and suppress it, thereby specifically killing cancer cells with that mutation.

[0004] Studies have shown that wRNAs are the "synthetic lethal partner" for high microsatellite instability (MSI-H), a genomic injury. MSI-H is a highly variable state caused by frequent insertions and / or deletions in nucleotide repeat regions due to defects in DNA mismatch repair (MMR), commonly found in cancers such as endometrial cancer (31%), colorectal cancer (25%), and gastric cancer (19%). In MSI-H cancer cells, thymine / adenine dinucleotide (TA) repeat sequences are highly unstable and undergo massive amplification, forming non-classical right-handed double helix (non-B) DNA secondary structures (e.g., cruciform and G-quadruplex). These DNA secondary structures require specific unwinding by wRNAs to complete replication. In the absence of WRN, these DNA secondary structures are cleaved by the MUS81-EME1-SLX4 endonuclease complex, leading to extensive DNA end removal, depletion of replication protein A (RPA), chromosome fragmentation, and cell death. Furthermore, in tumor models with MMR deficiency, WRN loss activates multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, thereby inhibiting tumor cell proliferation. Recent studies have shown that small molecule WRN inhibitors specifically induce tumor regression in MSI-H tumor models, but have no effect in microsatellite stable (MSS) tumor models. Therefore, small molecule chemotherapeutic drugs that inhibit WRN helicase activity hold promise as a novel approach for effectively treating MSI-H cancers.

[0005] No new inhibitors targeting WRN have been launched, nor is there any information on clinical compounds. As a cutting-edge research area, there is still enormous room for exploration in WRN-target research, and it is essential to continue developing new inhibitors. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0007]

[0008] in:

[0009] key express It can exist as a (Z)- or (E)- stereoisomer, where -* indicates a connection point;

[0010] X is selected from CR a Or N;

[0011] Y is selected from CR b Or N;

[0012] Z is selected from CR c Or N;

[0013] R a Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 Substituents of alkoxy groups;

[0014] R b Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0015] R c Selected from hydrogen atoms, C 1-6 Alkyl, -NR 6 R 7 or -N(R) 6 )C(=O)R 7 ;

[0016] W is selected from O or NR e ;

[0017] R e Selected from hydrogen atom, deuterium atom, cyano group, C 1-6 Alkyl, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 6-10 The aryl or 5-6 heteroaryl group may be further selected from one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0018] R 4 Selected from -OR 5 -NR 6 R 7 3-10 membered heterocyclic groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl; wherein the 3-10 membered heterocyclic group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0019] R 1 Selected from hydrogen atoms, C 3-8 cycloalkyl, -OR A Or S(O) r R A The C mentioned therein 3-8 The cycloalkyl group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced;

[0020] R A Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups may be further substituted with one or more R groups. AA replace

[0021] R AA Selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl, 5-6 heteroaryl, =O, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0022] Or, two Rs AA Together with the same carbon atom it is attached to, it forms a -C (=O);

[0023] Or, two Rs AATogether with the same carbon atom it is attached to, they form a C 3-8 Cycloalkyl or 3-10 membered heterocyclic group; wherein the C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups may be selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0024] R 2 Selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0025] Or, R 2 and X, R 2 Each of Y and its bonded atoms independently forms a 5-6 aryl or heteroaryl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0026] R d Selected from hydrogen atoms, C 1-6 Alkyl or C 0-6 Alkylene-R B ;

[0027] R B Selected from hydroxyl, alkenyl, alkynyl, cyano, C 3-12 cycloalkyl, C 6-10 aryl, 3-12 heterocyclic, 5-10 membered heteroaryl, or 8-10 membered fused ring, wherein the alkenyl, alkynyl, C 3-12 cycloalkyl, C 6-10 Aryl, 3-12 heterocyclic, 5-10 heteroaryl, or 8-10 fused ring may be further coupled with one or more R C Replaced;

[0028] R C Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 quinone heteroaryl, optionally further substituted by one or more R D Replaced;

[0029] Or, two Rs C Together with the same carbon atom it is attached to, it forms a -C (=O);

[0030] R D Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10The substituents are replaced;

[0031] Or, two Rs D Together with the same carbon atom it is attached to, it forms a -C (=O);

[0032] R f Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10-membered heterocyclic groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0033] R g Each atom is independently selected from hydrogen atoms or deuterium atoms, preferably hydrogen atoms;

[0034] R 3a R 3b Each is independently selected from hydrogen atoms, deuterium atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group; wherein the C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, or C. 1-6 Substituents of alkoxy groups;

[0035] The condition is that when W is 0, and R... 4 C is an optional replacement 1-6 Alkyl or optionally substituted C 3-8 When cycloalkyl, R 3a R 3b They are not both hydrogen atoms;

[0036] R 5 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10aryl or 5-6 heteroaryl groups may be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0037] R 6 and R 7 Each is independently selected from hydrogen atoms, hydroxyl groups, and C atoms. 1-6 Alkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups may be further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0038] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O).r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0039] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Substituted by aryl, 5-6 membered heteroaryl, carboxyl or carboxylic acid ester groups;

[0040] r can be 0, 1, or 2 independently;

[0041] Formula (I) does not contain the following compounds:

[0042]

[0043] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein W is selected from O;

[0044] R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; and R 3a R 3b They are not both hydrogen atoms;

[0045] R 4 Selected from C 1-6 Alkyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

[0046] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein W is selected from O;

[0047] R 3a It is a hydrogen atom;

[0048] R 3b Selected from deuterium atoms, halogens, cyano groups, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl;

[0049] R 4 Selected from C 1-6 Alkyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

[0050] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from O; R 3b Hydrogen atom

[0051] R 3a Selected from deuterium atoms, halogens, cyano groups, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl.

[0052] R 4 Selected from C 1-6 Alkyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

[0053] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein:

[0054] W is selected from O;

[0055] R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; preferably, R 3a R 3b It is a hydrogen atom;

[0056] R 4 Selected from C 2-6 alkenyl, C 2-6 Alkyne group, -OR 5 -NR 6 R 7 Or a 3-10 member heterocyclic group, wherein the C 2-6 alkenyl, C 2-6 The alkynyl or 3-10 membered heterocyclic group may optionally be further selected from one or more deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0057] R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl.

[0058] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from NR. e Re Selected from hydrogen atom, deuterium atom, or C atom 1-6 Alkyl, preferably, R e Selected from hydrogen atoms or C 1-6 Alkyl, more preferably, the C 1-6 Alkyl groups are preferably methyl groups;

[0059] R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; preferably, R 3a R 3b It is a hydrogen atom;

[0060] R 4 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be further selected from one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

[0061] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R d It is a hydrogen atom.

[0062] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R f Selected from C 3-8 Cycloalkyl, preferably cyclopropyl.

[0063] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OR A ,

[0064] R A Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-10 membered heterocyclic or C 6-10Aryl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group is optionally further modified by an R AA replace;

[0065] R AA Selected from C 3-8 cycloalkyl;

[0066] Or, two Rs AA Together with the same carbon atom it is attached to, they form a C 3-8 Cycloalkyl.

[0067] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OR A R A Selected from the following groups:

[0068]

[0069] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein Z is selected from CR c Or N, R c It is a hydrogen atom.

[0070] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein X is selected from CR a Or N, R a It is a hydrogen atom.

[0071] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein Y is selected from CR b Or N,

[0072] R b Selected from hydrogen atom, halogen, deuterium atom, nitro group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 5 -NR 6 R 7 -C(=O)R 5 -S (=O) r R 5 3-10 heterocyclic group, C 3-8 cycloalkyl, 5-6-membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-8 Cycloalkyl, 3-10 heterocyclic, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkyl halogenates are substituted.

[0073] R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl;

[0074] r is 2.

[0075] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein Y is selected from CR b R b Selected from the following groups: hydrogen atom, deuterium atom, fluorine, chlorine, bromine, hydroxyl, methoxy, amino, dimethylamino, vinyl, ethynyl.

[0076] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 2 Selected from SF5, hydroxyl, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further replaced by one or more halogens.

[0077] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 2 Selected from SF5 or

[0078] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0079]

[0080]

[0081] Or its stereoisomers, tautomers, or medicinal salts.

[0082] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0083] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0084] The present invention provides the use of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a WRN inhibitor.

[0085] The present invention also provides the use of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating WRN-mediated diseases, wherein the WRN-mediated diseases are preferably highly microsatellite unstable (MSI-H) cancers; wherein the WRN-mediated diseases are selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0086] The present invention further provides the use of the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the preparation of a medicament for treating highly microsatellite unstable (MSI-H) cancer.

[0087] This invention provides the use of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically usable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, melanoma of the skin, squamous cell carcinoma of the lung, prostate cancer, lung adenocarcinoma, transitional cell carcinoma of the bladder, neuroblastoma of children, chronic lymphocytic leukemia or glioma, preferably in the preparation of medicaments for treating colorectal cancer, gastric cancer or endometrial cancer.

[0088] Detailed description of the invention

[0089] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0090] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0091] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C6 alkenyl is preferred, and C2-C4 alkenyl is more preferred. The alkenyl group may be optionally substituted or unsubstituted.

[0092] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0093] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0094] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

[0095] Monocyclic alkyl groups can be substituted or unsubstituted.

[0096] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0097] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0098] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged cycloalkyl groups can be substituted or unsubstituted.

[0099] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having 3 to 8-membered monocyclic or 5 to 18-membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0100] The heterocyclic group can be substituted or unsubstituted.

[0101] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, azabolane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0102] "Spirocyclone" refers to a polycyclic aromatic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0103] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0104] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0105] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0106] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0107] The heteroaryl group can be substituted or unsubstituted.

[0108] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r (where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0109]

[0110] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0111] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0112] "Nitro" refers to the -NO2 group.

[0113] "Hydroxy" refers to the -OH group.

[0114] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0115] "Amino" refers to -NH2.

[0116] "Hydroxyamino group" refers to -NHOH.

[0117] “Cyano” refers to -CN.

[0118] "Benzyl" refers to -CH2-phenyl.

[0119] "Carboxyl group" refers to -C(=O)OH.

[0120] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0121] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0122] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0123] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0124] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0125] "DMSO" refers to dimethyl sulfoxide.

[0126] “BOC” refers to tert-butoxycarbonyl.

[0127] “Bn” refers to benzyl.

[0128] "THP" refers to 2-tetrahydropyranyl.

[0129] "TFA" refers to trifluoroacetic acid.

[0130] “Ts” refers to p-toluenesulfonyl group.

[0131] “Bn” refers to benzyl.

[0132] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0133] "Formyl group" refers to

[0134] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0135] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0136] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, SF5, =O, -OR 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -CH2NHC(=O)OR 5 -CH2NR 6 R 7 -S (=O)r NR 6 R 7 or -S(O) r R 5 The substituents are replaced;

[0137] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0138] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0139] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0140] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0141] r can be 0, 1, or 2 independently.

[0142] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0143] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0144] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0145] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0146] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0147] Example

[0148] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0149] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0150] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0151] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0152] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0153] CD3OD: Deuterated methanol.

[0154] CDCl3: Deuterated chloroform.

[0155] DMSO-d6: Deuterated dimethyl sulfoxide.

[0156] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0157] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0158] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0159] Example 1

[0160] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-

[0161] phenoxypyrimidine-5-carboxamide

[0162] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0163]

[0164] first step

[0165] ethyl 2-(methylthio)-4-phenoxypyrimidine-5-carboxylate

[0166] 2-(methylthio)-4-phenoxypyrimidine-5-carboxylic acid ethyl ester

[0167] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid 1a (10 g, 42.98 mmol, commercially available) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (11.88 g, 85.95 mmol) and phenol (5.06 g, 53.72 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 2-(methylthio)-4-phenoxypyrimidine-5-carboxylic acid 1b (8 g), yield 64.11%.

[0168] MS m / z(ESI): 291.0 [M+H] +

[0169] 1 H NMR(400MHz, CDCl3)δ8.92(s,1H),7.48–7.35(m,2H),7.26–7.21(m,1H),7. 19–7.13(m,2H),4.41(q,J=7.1Hz,2H),2.23(s,3H),1.40(t,J=7.1Hz,4H).

[0170] Step 2

[0171] ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate

[0172] 2-Chloro-4-phenoxypyrimidine-5-carboxylic acid ethyl ester

[0173] Ethyl 2-(methylthio)-4-phenoxypyrimidine-5-carboxylic acid ester 1b (8 g, 27.55 mmol) was dissolved in acetonitrile (100 mL), and a solution of sulfonyl chloride (55.78 g, 413.31 mmol) in dichloromethane (100 mL) was slowly added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was slowly poured into a cold sodium bicarbonate solution (500 mL), and extracted with dichloromethane (150 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylic acid ester 1c (6 g), with a yield of 78.13%.

[0174] MS m / z(ESI): 279.0 [M+H] +

[0175] 1 H NMR (400MHz, CDCl3) δ8.99(d,J=3.8Hz,1H),7.51–7.39(m,2H),7.35–7.27(m,1H),7.21–7.12(m,2H),4.44(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H).

[0176] Step 3

[0177] ethyl 4-phenoxy-2-(prop-1-en-2-yl)pyrimidine-5-carboxylate

[0178] 4-Phenoxy-2-(prop-1-en-2-yl)pyrimidin-5-carboxylic acid ethyl ester

[0179] Under a nitrogen atmosphere, ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate 1c (5 g, 17.94 mmol), potassium isopropenyltrifluoroborate 1d (3.98 g, 26.91 mmol), and sodium carbonate (3.80 g, 35.88 mmol) were added to a mixture of 1,4-dioxane (60 mL) and water (15 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.33 g, 1.79 mmol). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with water (100 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1e (3.14 g) of ethyl 4-phenoxy-2-(prop-1-en-2-yl)pyrimidine-5-carboxylate.

[0180] MS m / z (ESI): 285.2 [M+H] +

[0181] 1 H NMR(400MHz, CDCl3)δ9.11(s,1H),7.46–7.37(m,2H),7.26–7.23(m,1H),7.21–7.17(m,2 H), 6.26 (s, 1H), 5.48 (s, 1H), 4.43 (q, J = 7.1Hz, 2H), 2.02 (s, 3H), 1.41 (t, J = 7.0Hz, 3H).

[0182] Step 4

[0183] ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate

[0184] 2-Acetyl-4-phenoxypyrimidine-5-carboxylic acid ethyl ester

[0185] Ethyl 4-phenoxy-2-(prop-1-en-2-yl)pyrimidine-5-carboxylate 1e (1 g, 3.52 mmol) was dissolved in dichloromethane (10 mL), and ozone was bubbled through the solution at -78 °C for 30 minutes. Dimethyl sulfide (437.09 mg, 7.03 mmol) was then added at the current temperature, and the mixture was stirred for 30 minutes, followed by stirring at room temperature for 1 hour. The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (eluent: system A) to give ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate 1f (377 mg), in 37.44% yield.

[0186] MS m / z(ESI): 287.0 [M+H] +

[0187] 1 H NMR (400MHz, CDCl3) δ9.25 (s, 1H), 7.49–7.43 (m, 2H), 7.30 (t, J = 7.4Hz, 1H), 7.23–7.19(m,2H),4.47(q,J=7.1Hz,2H),2.46(s,3H),1.44(t,J=7.1Hz,3H).

[0188] Step 5

[0189] ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate

[0190] 2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid ethyl ester

[0191] 1g (200mg, 0.70mmol) of ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate was added to a solution of diethylaminotrifluoride in dichloromethane (5mL), and stirred at 25°C for 16 hours. The mixture was quenched with saturated sodium bicarbonate solution (10mL). Extraction was performed with dichloromethane (10mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (eluent: system A) to give 1g (180mg) of ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate, in 83% yield.

[0192] MS m / z(ESI): 309.0 [M+H] +

[0193] Step 6

[0194] 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid

[0195] 2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid

[0196] Lithium hydroxide (42 mg, 1.75 mmol) was added to a solution of 1 g (180 mg, 0.58 mmol) of ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid in tetrahydrofuran (4 mL) and water (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to pH 6 with 0.5 M hydrochloric acid at 0 °C, extracted with ethyl acetate (10 mL × 3), the organic layer was dried over sodium sulfate, filtered and concentrated to give 1 h (100 mg) of 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid, yield 61%.

[0197] LCMS:MS m / z(ESI):281.0[M+H] +

[0198] 1 H NMR (400MHz, CDCl3) δ9.35 (s, 1H), 7.51–7.38 (m, 2H), 7.35–7.28 (m, 1H), 7.23–7.15 (m, 2H), 1.84 (t, J = 18.5Hz, 3H).

[0199] Step 7

[0200] diethyl(fluoro(methylsulfonyl)methyl)phosphonate

[0201] Diethyl(fluoro(methylsulfonyl)methyl)phosphonate

[0202] At -78°C, bis(trimethylsilyl)amino potassium (1.0 mol / L THF) (1 M, 3.62 mL, 3.62 mmol) was added dropwise to a tetrahydrofuran solution (10 mL) of diethyl((methanesulfonyl)methyl)phosphonate 1i (640 mg, 2.78 mmol, commercially available). The reaction mixture was stirred at -78°C for half an hour, and then 1-(chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane difluoroborate (1.48 g, 4.18 mmol) was added. The reaction mixture was then heated to 25°C and stirred for 2 hours. After the reaction was complete, the mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give diethyl(fluoro(methylsulfonyl)methyl)phosphonate 1j (600 mg), with a yield of 86.82%.

[0203] MS(ESI,pos.ion)m / z:249.0[M+H]+.

[0204] Step 8

[0205] tert-butyl(E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamate

[0206] (E)-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)tert-butyl carbamate

[0207] Potassium carbonate (433 mg, 3.14 mmol) was added to a solution of N-(1-cyclopropyl-2-oxoethyl)carbamate tert-butyl 1k (250 mg, 1.25 mmol, commercially available) and diethyl(fluoro(methanesulfonyl)methyl)phosphonate 1j (311 mg, 1.25 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at 60 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (E)-(1-cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)carbamate tert-butyl 1l (200 mg), yield 54.34%. MS(ESI,pos.ion)m / z:238.0[M-56+H]+

[0208] Step 9

[0209] (E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl)prop-2-en-1-amine

[0210] (E)-1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)prop-2-en-1-amine

[0211] A solution of 1 L (140 mg, 477 μmol) of tert-butyl (E)-(1-cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)carbamate in dichloromethane (3 mL) was added to 1 mL of trifluoroacetic acid, and the resulting mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to dryness under reduced pressure to give 1 M (90 mg) of (E)-1-cyclopropyl-3-fluoro-3-(methanesulfonyl)prop-2-en-1-amine, in a yield of 97.59%.

[0212] MS(ESI,pos.ion)m / z:194.0[M+H] +

[0213] Step 10

[0214] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-

[0215] phenoxypyrimidine-5-carboxamide

[0216] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0217] To a solution of 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid 1 h (130 mg, 463 μmol, commercially available) and (E)-1-cyclopropyl-3-fluoro-3-(methanesulfonyl)prop-2-en-1-amine 1 m (89 mg, 463 μmol) in N,N-dimethylformamide (3 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (353 mg, 928 μmol) and N,N-diisopropylethylamine (300 mg, 2.32 mmol) were added, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (Nouryon-Kromasil-C) 18Purification at -10um-25*250mm (elution buffer: 10% to 90% (v / v) CH3CN and H2O, NH4HCO3 0.025%) yielded (E)-N-(1-cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide 1 (107 mg), yield 50.64%.

[0218] MS(ESI,pos.ion)m / z:456.1[M+H]+

[0219] 1H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.95(d,J=8.0Hz,1H),7.54–7.49(m,2H),7.37–7.31(m,3H),6.35(dd,J=34.4,8.8Hz ,1H),4.49(q,J=8.4Hz,1H),3.27(s,3H),1.87(t,J=19.2Hz,3H),1.31–1.22(m,1H),0.59–0.50(m,2H),0.49–0.36(m,2H).

[0220] Example 2

[0221] methyl(E)-3-cyclopropyl-3-(2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamido)prop-1-

[0222] ene-1-sulfonate

[0223] (E)-3-Cyclopropyl-3-(2-(1,1-difluoroethyl)-4-phenoxypyrimidin-5-carbamoyl)prop-1-ene-1-sulfonate methyl ester

[0224] first step

[0225] methyl(diphenoxyphosphoryl)methanesulfonate

[0226] Methyl (diphenoxyphosphoryl)methyl sulfonate

[0227] Methyl methanesulfonate 2b (1 g, 9.08 mmol, commercially available) was dissolved in tetrahydrofuran (20 mL), and n-butyllithium (2.5 M, 4.36 mL) was added at -78 °C. The reaction was continued at -78 °C for 0.5 h. Diphenyl chlorophosphate 2a (1.34 g, 4.99 mmol, commercially available) was slowly added dropwise to the reaction solution, and the reaction was continued at -78 °C for 1 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl (diphenyloxyphosphoryl)methanesulfonate 2c (1.6 g), yield 51.48%.

[0228] 1H NMR (400MHz, CDCl3) δ7.39(m,4H),7.30–7.24(m,6H),4.08(s,1H),4.04(s,1H).

[0229] Step 2

[0230] methyl(E)-3-((tert-butoxycarbonyl)amino)-3-cyclopropylprop-1-ene-1-sulfonate

[0231] (E)-3-((tert-butoxycarbonyl)amino)-3-cyclopropylpropyl-1-ene-1-sulfonate methyl ester

[0232] Methyl (diphenyloxyphosphoryl)methanesulfonate 2c (577 mg, 1.69 mmol) and N-(1-cyclopropyl-2-oxoethyl)carbamate tert-butyl 1k (280 mg, 1.41 mmol) were dissolved in tetrahydrofuran (5 mL), followed by the addition of potassium carbonate (486 mg, 3.51 mmol). The reaction mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: system A) to give (E)-3-((tert-butoxycarbonyl)amino)-3-cyclopropylpropyl-1-ene-1-sulfonate methyl ester 2d (250 mg), yield 61.06%.

[0233] MS(ESI,pos.ion)m / z:236.0[M+H]+

[0234] Step 3

[0235] methyl(E)-3-amino-3-cyclopropylprop-1-ene-1-sulfonate

[0236] (E)-3-amino-3-cyclopropylpropyl-1-ene-1-sulfonate methyl ester

[0237] Methyl (E)-3-((tert-butoxycarbonyl)amino)-3-cyclopropylprop-1-ene-1-sulfonate 2d (250 mg, 858.04 μmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (1 mL). The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to give methyl (E)-3-amino-3-cyclopropylprop-1-ene-1-sulfonate 2e (160 mg), with a yield of 97.50%.

[0238] MS(ESI,pos.ion)m / z:192.1[M+H] +

[0239] Step 4 methyl(E)-3-cyclopropyl-3-(2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamido)prop-1-ene-1-sulfonate

[0240] (E)-3-Cyclopropyl-3-(2-(1,1-difluoroethyl)-4-phenoxypyrimidin-5-carbamoyl)prop-1-ene-1-sulfonate methyl ester

[0241] Methyl (E)-3-amino-3-cyclopropylpropyl-1-ene-1-sulfonate 2e (124 mg, 649.47 μmol), 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid 1h (140 mg, 499.60 μmol), and N,N-diisopropylethylamine (323 mg, 2.5 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (285 mg, 749.39 μmol, commercially available). The reaction mixture was then reacted at 25 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residues were separated by preparative high-performance liquid chromatography (Nouryon-Kromasil-C). 18 -10um-25*250mm (elution buffer: 10% to 90% (v / v) CH3CN and H2O, NH4HCO3 for 0.025%), to give methyl (E)-3-cyclopropyl-3-(2-(1,1-difluoroethyl)-4-phenoxypyrimidin-5-carbamoyl)prop-1-ene-1-sulfonate 2 (18 mg), yield 7.95%.

[0242] MS(ESI,pos.ion)m / z:454.1[M+H] +

[0243] 1H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.94(d,J=8.0Hz,1H),7.57–7.41(m,3H),7.32(m,4H),6.99(m,1H),6.7 6(m,1H),4.30(m,1H),3.72(s,3H),1.86(m,17.4Hz,3H),1.13(m,1H),0.58–0.49(m,3H),0.45–0.38(m,1H).

[0244] Example 3

[0245] (S,E)-N-(1-cyclopropyl-3-(N-methylsulfamoyl)allyl)-2-(1,1-difluoroethyl)-4-

[0246] phenoxypyrimidine-5-carboxamide

[0247] (S,E)-N-(1-Cyclopropyl-3-(N-Methylsulfonamido)allyl)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0248]

[0249]

[0250] first step

[0251] diphenyl((N-methylsulfamoyl)methyl)phosphonate

[0252] Diphenyl((N-methylsulfonamide)methyl)phosphonate

[0253] At -78°C, 4.70 g of butyllithium / hexane (73.30 mmol) was added to a tetrahydrofuran (80 mL) solution of N-methylmethanesulfonamide 3a (4 g, 36.65 mmol), and the mixture was stirred for 1 hour. Then, a tetrahydrofuran (80 mL) solution of diphenyl chlorophosphate 2a (4.92 g, 18.32 mmol) was added dropwise, and the mixture was reacted at -78°C for 1.5 hours, with the reaction monitored for completeness. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give diphenyl((N-methylsulfonamide)methyl)phosphonate 3b (2.36 g), yield 18.87%.

[0254] MS m / z(ESI): 342.0 [M+1]

[0255] Step 2

[0256] tert-butyl(S,E)-(1-cyclopropyl-3-(N-methylsulfamoyl)allyl)carbamate

[0257] (S,E)-(1-Cyclopropyl-3-(N-Methylsulfonamido)allyl)tert-butyl carbamate

[0258] At room temperature, diphenyl((N-methylsulfonamide)methyl)phosphonate 3b (500 mg, 1.46 mmol), (S)-(1-cyclopropyl-2-oxoethyl)carbamate butyl 3c (321.06 mg, 1.61 mmol, commercially available), and potassium carbonate (607.39 mg, 4.39 mmol) were added to tetrahydrofuran (10 mL), purged with argon, and reacted at 60 °C for 3 hours. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: C system) to give (S,E)-(1-cyclopropyl-3-(N-methylsulfonamide)allyl)carbamate tert-butyl 3d (80 mg), yield 18.81%.

[0259] MS m / z(ESI): 235.1 [M-56+1]

[0260] Step 3

[0261] (S,E)-3-amino-3-cyclopropyl-N-methylprop-1-ene-1-sulfonamide

[0262] (S,E)-3-amino-3-cyclopropyl-N-methylprop-1-ene-1-sulfonamide

[0263] At room temperature, 1 mL of trifluoroacetic acid was added to a solution of (S,E)-(1-cyclopropyl-3-(N-methylsulfonamido)allyl)carbamate tert-butyl 3d (80 mg, 275.50 μmol) in dichloromethane (5 mL), and the reaction was allowed to proceed for 40 minutes at room temperature. After monitoring for complete reaction, the solution was concentrated under reduced pressure to give (S,E)-3-amino-3-cyclopropyl-N-methylprop-1-ene-1-sulfonamide 3e (52 mg), yield 99.20%. MS m / z (ESI): 191.1 [M+1]

[0264] Step 4

[0265] (S,E)-N-(1-cyclopropyl-3-(N-methylsulfamoyl)allyl)-2-(1,1-difluoroethyl)-4-

[0266] phenoxypyrimidine-5-carboxamide

[0267] (S,E)-N-(1-Cyclopropyl-3-(N-Methylsulfonamido)allyl)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0268] At room temperature, 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid 1h (60 mg, 214.11 μmol), (S,E)-3-amino-3-cyclopropyl-N-methylprop-1-ene-1-sulfonamide 3e (52.96 mg, 278.35 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (162.82 mg, 428.23 μmol), and N,N-diisopropylethylamine (138.36 mg, 1.07 mmol) were added to N,N-dimethylformamide (3 mL) and reacted at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give (S,E)-N-(1-cyclopropyl-3-(N-methylsulfonamido)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide 3 (1.76 mg), yield 1.74%.

[0269] MS m / z(ESI): 453.1 [M+1]

[0270] 1H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.89(d,J=8.2Hz,1H),7.49(dd,J=8.5,7.3Hz,2H),7.42–7.27( m,3H),7.03(q,J=5.0Hz,1H),6.66(dd,J=15.2,5.2Hz,1H),6.49(dd,J=15.3,1.5Hz,1H),4.28(tdd, J=8.3,5.2,1.6Hz,1H),2.41(d,J=4.7Hz,3H),1.86(t,J=19.0Hz,3H),1.11(tdd,J=8.1,5.4,3.1Hz, 1H),0.60–0.54(m,1H),0.54–0.49(m,1H),0.46(dd,J=6.8,3.6Hz,1H),0.41(dd,J=8.4,5.1Hz,1H).

[0271] Example 4

[0272] (Z)-N-(3-bromo-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-

[0273] phenoxypyrimidine-5-carboxamide

[0274] (Z)-N-(3-bromo-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0275]

[0276]

[0277] first step

[0278] diethyl(bromo(methylsulfonyl)methyl)phosphonate

[0279] Diethylbromo(methylsulfonyl)methylphosphonate

[0280] Compound 1i (200 mg, 868.74 μmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (104 mg, 2.6 mmol, 60% purity) was added at 0 °C, and the reaction was allowed to proceed for 0.5 h. Liquid bromine (153 mg, 955.62 μmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction solution, and the reaction was continued at 0 °C for 2 h. After the reaction was completed, the solution was quenched with anhydrous sodium sulfite solution, extracted with dichloromethane (20 mL × 3), the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give compound 4b (130 mg), with a yield of 48.41%. 1 H NMR (400MHz, CDCl3) δ4.78–4.65(m,1H),4.38–4.25(m,4H),3.33(s,3H),1.39(m,6H).

[0281] Step 2

[0282] tert-butyl(Z)-(3-bromo-1-cyclopropyl-3-(methylsulfonyl)allyl)carbamate

[0283] tert-butyl(Z)-(3-bromo-1-cyclopropyl-3-(methylsulfonyl)allyl)carbamate

[0284] 4b (101 mg, 326.23 μmol) and 1k (50 mg, 250.95 μmol, commercially available) were dissolved in tetrahydrofuran (3 mL), and potassium carbonate (104 mg, 752.84 μmol) was added. The mixture was then reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with dichloromethane (20 mL × 3). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system A for purification) to give compound 4d (22 mg), yield 24.75%.

[0285] MS(ESI,pos.ion)m / z:378.1[M+Na] +

[0286] Step 3

[0287] (Z)-3-bromo-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine

[0288] (Z)-3-Bromo-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine

[0289] 4d (22 mg, 62.10 μmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (1 mL), and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give 4e (15 mg), with a yield of 95.04%.

[0290] MS(ESI,pos.ion)m / z:256.0[M+H] +

[0291] Step 4

[0292] (Z)-N-(3-bromo-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-

[0293] phenoxypyrimidine-5-carboxamide

[0294] (Z)-N-(3-bromo-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0295] 4e (15 mg, 59.02 μmol), 1h (20 mg, 70.83 μmol) and N,N-diisopropylethylamine (38 mg, 295.11 μmol) were dissolved in N,N-dimethylformamide (1 mL), and then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 88.53 μmol) was added. The mixture was then reacted at 25 °C for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate (20 mL × 3). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Nouryon-Kromasil column; 250 × 25 mm; 10 μm, 30 mL / min; mobile phase A: 0.1% NH4HCO3 + H2O, mobile phase B: CH3CN) to give compound 4 (14 mg), yield 45.94%. MS (ESI, pos.ion) m / z: 518.0 [M + H] +

[0296] 1 H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 8.95 (d, J = 8.0Hz, 1H), 7.52 (m, 2H), 7.35 (m, 4H ),4.57(m,1H),3.21(s,3H),1.87(t,J=19.2Hz,3H),1.22(m,1H),0.57–0.45(m,4H).

[0297] Example 5

[0298] (E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-3-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0299] (E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl-3-deuterated)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0300]

[0301] first step

[0302] tert-butyl(E)-(1-cyclopropyl-3-(methylsulfonyl)allyl-3-d)carbamate

[0303] tert-butyl(E)-(1-cyclopropyl-3-(methylsulfonyl)allyl-3-deuterated)carbamate

[0304] Compound 4d (20 mg, 56.46 μmol), deuterated methanol (51 mg, 1.41 mmol), n-butylbis(1-adamantyl)phosphine (4 mg, 11.29 μmol, commercially available), and potassium phosphate (30 mg, 141.14 μmol) were dissolved in toluene (1 mL). Palladium acetate (1 mg, 4.46 μmol) was added under a nitrogen atmosphere, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give compound 5a (16 mg), in 100% yield.

[0305] MS m / z (ESI): 299.1 [M+Na] +

[0306] Step 2

[0307] (E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-3-d-1-amine

[0308] (E)-1-Cyclopropyl-3-(Methylsulfonyl)prop-2-en-3-deuterated-1-amine

[0309] Compound 5a (16 mg, 57.89 μmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (1 mL), and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 5b (10 mg), with a yield of 98%.

[0310] MS m / z(ESI): 177.0 [M+H] +

[0311] Step 3

[0312] (E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-3-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0313] (E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl-3-deuterated)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0314] Compound 5b (10 mg, 56.74 μmol), 1h (19 mg, 68.08 μmol), and N,N-diisopropylethylamine (37 mg, 283.68 μmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (32 mg, 85.10 μmol). The reaction mixture was then reacted at 25 °C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL × 3). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Nouryon-Kromasil column; 250 × 25 mm; 10 μm, 30 mL / min; mobile phase A: 0.1% NH4HCO3 + H2O, mobile phase B: CH3CN) to give compound 5 (8 mg), yield 32%. MS m / z(ESI): 439.1 [M+H] +

[0315] H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 8.94 (d, J = 8.4Hz, 1H), 7.54–7.49 (m, 2H), 7.37–7.3 2(m,3H),6.90–6.86(m,1H),4.32(m,1H),3.00(s,3H),1.89(t,J=19.2Hz,3H),1.17–1.09

[0316] (m,1H),0.62–0.47(m,3H),0.41(m,1H).

[0317] Example 6

[0318] (E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0319] (E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl-2-deuterated)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0320]

[0321]

[0322] first step

[0323] tert-butyl(1-cyclopropyl-2-hydroxyethyl-2,2-d2)carbamate

[0324] tert-butyl (1-cyclopropyl-2-hydroxyethyl-2,2-dideuterated) carbamate

[0325] 6a (600 mg, 2.62 mmol) was dissolved in tetrahydrofuran (2 mL), and LiAlD4 (121 mg, 2.88 mmol) was added at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 hour, quenched with sodium sulfate decahydrate and stirred for 1 hour, then filtered and the filter cake was washed with dichloromethane (20 mL × 3). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give compound 6b (500 mg) in 93.99% yield.

[0326] MS(ESI,pos.ion)m / z:148.1[M+H-56] +

[0327] Step 2

[0328] tert-butyl(1-cyclopropyl-2-oxoethyl-2-d)carbamate

[0329] tert-butyl (1-cyclopropyl-2-hydroxyethyl-2-deuterated) carbamate

[0330] Compound 6b (640 mg, 3.15 mmol) was dissolved in dichloromethane (10 mL) and (1,1-diacetoxy-3-oxo-1,2-benzoxo-1-yl)acetate (2.00 g, 6.45 mmol, commercially available) was added. The resulting mixture was stirred at 25 °C for 1 hour. The mixture was then poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give compound 6c (250 mg) in 39.65% yield.

[0331] MS(ESI,pos.ion)m / z:145.2[M+H-56] +

[0332] Step 3

[0333] tert-butyl(E)-(1-cyclopropyl-3-(methylsulfonyl)allyl-2-d)carbamate

[0334] tert-butyl(E)-(1-cyclopropyl-3-(methylsulfonyl)allyl-2-deuterated)carbamate

[0335] Potassium carbonate (396 mg, 2.87 mmol) was added to a solution of 6c (230 mg, 1.15 mmol) and 1-[ethoxy(methanesulfonylmethyl)phospho]oxyethane (291 mg, 1.26 mmol, commercially available) in tetrahydrofuran (2 mL). The resulting mixture was stirred at 60 °C for 2 hours, poured into water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give compound 6d (200 mg), in a yield of 63.01%.

[0336] MS(ESI,pos.ion)m / z:221.0[M+H-56] +

[0337] Step 4

[0338] (E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-2-d-1-amine

[0339] (E)-1-Cyclopropyl-3-(Methylsulfonyl)propyl-2-enyl-2-deuterated-1-amine

[0340] A solution of 6d (100 mg, 361.83 μmol) in dichloromethane (3 mL) was added to trifluoroacetic acid (1 mL). The resulting mixture was stirred for 1 hour, and then concentrated to dryness under reduced pressure to give compound 6e (60 mg), with a yield of 94.08%.

[0341] MS(ESI,pos.ion)m / z:177.0[M+H] +

[0342] Step 5

[0343] (E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0344] (E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl-2-deuterated)-2-(1,1-Difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[0345] To a 1h (100 mg, 356.85 μmol) and 6e N,N-dimethylformamide (2 mL) solution, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (271 mg, 713.71 μmol) and N,N-diisopropylethylamine (230 mg, 1.78 mmol, commercially available) were added. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was then poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative liquid chromatography (Nouryon-Kromasil-C18-10 μm-25×250 mm column (eluent: 10%-90% (v / v) acetonitrile and water (containing 0.025% ammonium bicarbonate)) to give compound 6 (112 mg), yield 71.58%.

[0346] MS(ESI,pos.ion)m / z:439.1[M+H] +

[0347] 1H NMR(400MHz, DMSO-d6)δ9.04(s,1H),8.94(d,J=8.4Hz,1H),7.55–7.49(m,2H),7.38–7.32(m,3H),6.90(d,J=1.6Hz,1H),4 .32(td,J=8.4,1.6Hz,1H),3.00(s,3H),1.89(t,J=20.0Hz,3H),1.18–1.09(m,1H),0.61–0.49(m,3H),0.44–0.38(m,1H).

[0348] Example 7

[0349] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-

[0350] phenoxynicotinamide

[0351] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide

[0352]

[0353]

[0354] first step

[0355] ethyl 2-phenoxy-6-(prop-1-en-2-yl)nicotinate

[0356] 2-Chloro-6-(prop-1-en-2-yl)nicotinic acid ethyl ester

[0357] Under an argon atmosphere, ethyl 2,6-dichloronicotinate 7a (1 g, 4.54 mmol), potassium isopropenyltrifluoroborate 1d (672.48 mg, 4.54 mmol), and sodium carbonate (1.44 g, 13.63 mmol) were added to a mixture of 1,4-dioxane (15 mL) and water (3 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (337.09 mg, 454.44 μmol). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (60 mL), filtered, and the filtrate was washed with water (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 2-chloro-6-(prop-1-en-2-yl)nicotinic acid 7b (1.0 g), yield 97.51%. MS m / z (ESI): 226.0 [M+H] + .

[0358] Step 2

[0359] ethyl 2-phenoxy-6-(prop-1-en-2-yl)nicotinate

[0360] 2-Phenoxy-6-(prop-1-en-2-yl)nicotinic acid ethyl ester

[0361] Ethyl 2-chloro-6-(prop-1-en-2-yl)nicotinic acid 7b (1.0 g, 4.43 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.88 g, 5.76 mmol) and phenol (542.14 mg, 5.76 mmol) were added. The mixture was stirred at 80 °C for 12 hours. After the reaction solution was brought to room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (60 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 2-phenoxy-6-(prop-1-en-2-yl)nicotinic acid 7c (517.0 mg), with a yield of 41.18%.

[0362] MS m / z(ESI): 284.0 [M+H] + .

[0363] Step 3

[0364] ethyl 6-acetyl-2-phenoxynicotinate

[0365] 6-Acetyl-2-phenoxynicotinic acid ethyl ester

[0366] Ethyl 2-phenoxy-6-(prop-1-en-2-yl)nicotinic acid 7c (517.0 mg, 1.82 mmol) was dissolved in a mixed solution of tetrahydrofuran (6 mL) and water (2 mL). Potassium (VI) osmium tetroxide dihydrate (67.23 mg, 182.48 μmol, commercially available) and sodium periodate (780.61 mg, 3.65 mmol) were added at 0 °C. The mixture was stirred at room temperature for 3 h. After the reaction was completed by TLC and MS, water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed successively with a saturated solution of sodium thiosulfate and a saturated sodium chloride solution (30 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography (eluent: system A) to give ethyl 6-acetyl-2-phenoxynicotinic acid 7d (275 mg), with a yield of 52.82%.

[0367] MS m / z(ESI): 286.0 [M+H] + .

[0368] Step 4

[0369] ethyl 6-(1,1-difluoroethyl)-2-phenoxynicotinate

[0370] 6-(1,1-Difluoroethyl)-2-phenoxynicotinic acid ethyl ester

[0371] Ethyl 6-acetyl-2-phenoxynicotinic acid ester 7d (275 mg, 963.92 μmol) was added to a solution of diethylaminotrifluoride in dichloromethane (5 mL) and stirred at 25 °C for 36 hours. The mixture was quenched with saturated sodium bicarbonate solution (10 mL). Extraction was performed with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 6-(1,1-difluoroethyl)-2-phenoxynicotinic acid ester 7e (255 mg), yield 86.09%.

[0372] MS m / z(ESI): 308.0 [M+H] + .

[0373] Step 5

[0374] 6-(1,1-difluoroethyl)-2-phenoxynicotinic acid

[0375] 6-(1,1-Difluoroethyl)-2-phenoxynicotinic acid

[0376] Lithium hydroxide (349.15 mg, 8.32 mmol) was added to a solution of ethyl 6-(1,1-difluoroethyl)-2-phenoxynicotinic acid 7e (255 mg, 832.11 μmol) in tetrahydrofuran (4 mL) and water (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to pH 6 with 0.5 M hydrochloric acid at 0 °C, extracted with ethyl acetate (10 mL × 3), the organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1,1-difluoroethyl)-2-phenoxynicotinic acid 7f (75 mg).

[0377] LCMS: MS m / z (ESI): 280.0 [M+H] + .

[0378] Step 6

[0379] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-

[0380] phenoxynicotinamide

[0381] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide

[0382] To a solution (3 mL) of 6-(1,1-difluoroethyl)-2-phenoxynicotinic acid 7f (75 mg, 268.59 μmol) and (E)-1-cyclopropyl-3-fluoro-3-(methanesulfonyl)prop-2-en-1-amine 1m (51.90 mg, 268.59 μmol) in N,N-dimethylformamide, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (153.19 mg, 402.88 μmol) and N,N-diisopropylethylamine (138.85 mg, 1.07 mmol) were added, and the mixture was stirred at 25 °C for 12 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (Nouryon-Kromasil-C) 18Purification with eluent: 10µm-25*250mm (10%-90% (v / v) acetonitrile and water (containing 0.025% ammonium bicarbonate) yielded (E)-N-(1-cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide 7 (8.84 mg), yield 7.21%.

[0383] MS(ESI,pos.ion)m / z:455.1[M+H] + .

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.83(m,1H),8.23(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.49–7.41(m,2H),7.25(m,3H),6.32(dd, J=34.4,8.8Hz,1H),4.48(q,J=8.3Hz,1H),3.24(s,3H),1.76(t,J=19.0Hz,3H),1.23(m,1H),0.51(m,2H),0.43–0.36(m,2H).

[0385] Example 8

[0386] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-4-

[0387] phenoxynicotinamide

[0388] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide

[0389] first step

[0390] methyl 6-bromo-4-phenoxynicotinate

[0391] 6-Bromo-4-phenoxynicotinic acid methyl ester

[0392] 6-Bromo-4-chloronicotinic acid methyl ester 8a (1.0 g, 4.43 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (2.32 g, 16.77 mmol) and phenol (526.02 mg, 5.59 mmol) were added. The mixture was stirred at 80 °C for 12 hours. After the reaction solution was brought to room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (60 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 6-bromo-4-phenoxynicotinic acid methyl ester 8b (1.38 g), with a yield of 80.13%.

[0393] MS m / z(ESI): 309.0 [M+H] + .

[0394] Step 2

[0395] methyl 4-phenoxy-6-(prop-1-en-2-yl)nicotinate

[0396] 4-Phenoxy-6-(propen-1-en-2-yl)nicotinic acid methyl ester

[0397] Under an argon atmosphere, methyl 6-bromo-4-phenoxynicotinate 8b (1.38 g, 4.48 mmol), potassium isopropenyltrifluoroborate 1d (662.75 mg, 4.48 mmol), and sodium carbonate (1.42 g, 13.44 mmol) were added to a mixture of 1,4-dioxane (20 mL) and water (10 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (332.22 mg, 447.87 μmol). The mixture was stirred at 90 °C for 6 hours. The reaction mixture was diluted with ethyl acetate (60 mL), filtered, and the filtrate was washed with water (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 4-phenoxy-6-(propen-1-en-2-yl)nicotinic acid 8c (1.17 g), yield 97.01%.

[0398] MS m / z(ESI): 270.0 [M+H] + .

[0399] Step 3

[0400] methyl 6-acetyl-4-phenoxynicotinate

[0401] 6-Acetyl-4-phenoxynicotinic acid methyl ester

[0402] 4-Phenoxy-6-(propen-1-en-2-yl)nicotinic acid methyl ester 8c (1.17 g, 4.34 mmol) was dissolved in a mixed solution of tetrahydrofuran (15 mL) and water (7 mL). Potassium (VI) osmium tetroxide dihydrate (192.10 mg, 521.36 μmol) and sodium periodate (2.79 g, 13.03 mmol) were added at 0 °C. The mixture was stirred at room temperature for 3 h. After the reaction was completed, water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed successively with a saturated solution of sodium thiosulfate and a saturated sodium chloride solution (30 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography (eluent: system A) to give 6-acetyl-4-phenoxynicotinic acid methyl ester 8d (390 mg), with a yield of 33.09%.

[0403] MS m / z(ESI): 272.0 [M+H] + .

[0404] Step 4

[0405] methyl 6-(1,1-difluoroethyl)-4-phenoxynicotinate

[0406] 6-(1,1-Difluoroethyl)-4-phenoxynicotinic acid methyl ester

[0407] 6-Acetyl-4-phenoxynicotinic acid methyl ester 8d (390 mg, 1.44 mmol) was added to a solution of diethylaminotrifluoride in dichloromethane (5 mL) and stirred at 25 °C for 36 hours. The mixture was quenched with saturated sodium bicarbonate solution (10 mL). Extraction was performed with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (eluent: system A) to give 6-(1,1-difluoroethyl)-4-phenoxynicotinic acid methyl ester 8e (440 mg).

[0408] MS m / z(ESI): 294.0 [M+H] + .

[0409] Step 5

[0410] 6-(1,1-difluoroethyl)-4-phenoxynicotinic acid

[0411] 6-(1,1-Difluoroethyl)-4-phenoxynicotinic acid

[0412] Lithium hydroxide (629.55 mg, 15.00 mmol) was added to a solution of methyl 6-(1,1-difluoroethyl)-4-phenoxynicotinic acid 8e (440 mg, 1.50 mmol) in tetrahydrofuran (6 mL) and water (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was then adjusted to pH 6 with 0.5 M hydrochloric acid at 0 °C, extracted with ethyl acetate (10 mL × 3), the organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1,1-difluoroethyl)-4-phenoxynicotinic acid 8f (289 mg).

[0413] LCMS: MS m / z (ESI): 280.0 [M+H] + .

[0414] Step 6

[0415] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-4-

[0416] phenoxynicotinamide

[0417] (E)-N-(1-Cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide

[0418] To a solution of 6-(1,1-difluoroethyl)-4-phenoxynicotinic acid 8f (100 mg, 358.12 μmol) and (E)-1-cyclopropyl-3-fluoro-3-(methanesulfonyl)prop-2-en-1-amine 1m (46.13 mg, 238.74 μmol) in N,N-dimethylformamide (3 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (136.17 mg, 358.12 μmol) and N,N-diisopropylethylamine (123.42 mg, 954.98 μmol) were added, and the mixture was stirred at 25 °C for 12 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (Nouryon-Kromasil-C) 18Purified at -10µm-25*250mm (elution buffer: 10% to 90% (v / v) CH3CN and H2O, NH4HCO3 0.025%), yielded (E)-N-(1-cyclopropyl-3-fluoro-3-(methanesulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide 8 (8.84 mg), yield 22.51%. MS (ESI, pos.ion) m / z: 455.1 [M+H] + .

[0419] 1 H NMR (400MHz, DMSO-d6) δ8.86(m,1H),8.77(s,1H),7.55(m,2H),7.37(m,1H),7.32–7.26(m,2H),6.87(s,1H),6.30(dd,J=3 4.3,8.8Hz,1H),4.47(q,J=8.4Hz,1H),3.24(s,3H),1.94(t,J=19.2Hz,3H),1.21(m,1H),0.51(m,2H),0.40–0.34(m,2H).

[0420] Biological evaluation

[0421] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the proliferation of SW48 cells.

[0422] The following methods were used to determine the effect of the compounds of this invention on the proliferation of SW48 cells. SW48 cells (MSI-H cells) were purchased from the ATCC cell bank in the United States and cultured in Leibovitz's L-15 (Gibco, catalog number 11415064) medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0423] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well into 96-well cell culture plates and cultured overnight at 37°C in an air incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 40 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0424] Compound numbering <![CDATA[IC 50 (nM)]]> 4 20.37 5 12.51 6 19.67 7 67.62

[0425] Conclusion: The compound of this invention has an IC50 inhibitory effect on the proliferation of SW48 cells. 50 <100nM, exhibiting good inhibitory effect.

[0426] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the proliferation of RL95-2 cells.

[0427] The following methods were used to determine the effect of the compounds of this invention on the proliferation of RL95-2 cells. RL95-2 cells (MSI-H cells) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in DMEM / F12 medium (Gibco, catalog number A4192001) containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0428] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well into 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 50 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0429] Conclusion: The compound of this invention has an IC50 inhibitory effect on the proliferation of RL95-2 cells. 50 <100nM, exhibiting good inhibitory effect.

[0430] Test Example 3: Determination of the inhibitory effect of the compound of the present invention on the proliferation of HCT116 cells.

[0431] The following methods were used to determine the effect of the compounds of this invention on the proliferation of HCT116 cells. HCT116 cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5a medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The assay was performed using the Luminescent CellViability Assay kit (Promega, catalog number G7573).

[0432] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with the above-mentioned culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 300 cells per well into 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The test compound was then added, and the cells were cultured for another 120 hours. After the culture, 50 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 value.

[0433] Compound numbering <![CDATA[IC 50 (nM)]]> 4 15.15 6 14.70

[0434] Conclusion: The compound of this invention has an IC50 inhibitory effect on the proliferation of HCT116 cells. 50 <50 nM, exhibiting good inhibitory activity. Test Example 4: Test of the inhibitory effect of the compound of this invention on WRN helicase activity.

[0435] The following method was used to determine the degree of inhibition of recombinant human WRN helicase activity by the compounds of the present invention under in vitro conditions.

[0436] The experimental procedure is briefly described as follows: The test compound was first dissolved in DMSO to prepare a stock solution, and then serially diluted using reaction buffer (25mM Tris-HCl Ph8.0, 5mM NaCl, 2mM MgCl2, 1mM TCEP, 0.1mg / mL BSA, 0.01% Triton X-100, 1mM DTT, 200uM ADP, 200uM ATP). The final concentration range of the test compound in the reaction system was 1000nM to 0.004nM. WRN protein (purchased from BPS, catalog number 101264) and fluorescent substrate (synthesized by Suzhou Genewiz Biotechnology Co., Ltd., sequences 5'-TGTGTGTGGTTCGCTGGG-(BHQ)-3' and 5'-(TAMRA)-CCCAGCGAACTGGTGTGTGT-3', internally annealed to obtain double-stranded fluorescent substrate) were prepared using reaction buffer. The reaction was carried out in 384-well microplates. First, the compound and recombinant human WRN protein (final concentration 5 nM) were added to the wells and incubated at room temperature for 30 minutes. Then, a fluorescent substrate (final concentration 100 nM) and Trap-10bp solution (synthesized by Suzhou Genewiz Biotechnology Co., Ltd., sequence 5'-GTTCGCTGGG-3', final concentration 1 μM) were added to the reaction solution and incubated at room temperature for 30 minutes. After incubation, the fluorescence intensity of each well was measured using a microplate reader in Fluorescence mode, with excitation and emission wavelengths set to 535 nm and 585 nm, respectively. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was obtained by nonlinear regression analysis using GraphPad Prism 9 software, with the compound concentration as the logarithm of the inhibition rate. 50 value.

[0437] Conclusion: The compounds of this invention inhibit WRN helicase activity at IC50 levels. 50 <10μM, exhibiting good inhibitory activity. Test Example 5: Pharmacokinetic experiment of the compound of this invention in mice.

[0438] CD-1 mice were used as test animals, and the plasma drug concentration at different time points after gavage administration of the compound of the present invention was determined by LC-MS / MS. The pharmacokinetic behavior of the compound of the present invention in mice was studied, and its pharmacokinetic characteristics were evaluated.

[0439] Drug preparation: Weigh a certain amount of drug, add an appropriate volume of DMA, sonicate to dissolve completely, then add appropriate volumes of 1,2PG, Labrasol and water in sequence, vortex to mix, and prepare a 1 mg / mL dosage form. The ratio of DMA:1,2PG:Labrasol:Water in the preparation is 10:30:20:40 (v:v:v:v).

[0440] Administration: Mice were fasted before administration, and the dosage was 10 mg / kg.

[0441] Procedure: Mice were administered the compound of this invention by gavage. At 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after administration, approximately 100 μL of blood was collected from the orbital cavity. The collected whole blood was placed in an EDTA-K2 anticoagulant tube, inverted several times to mix thoroughly, and stored on wet ice. Within 30 minutes, the sample was centrifuged (1500-1600g) for 10 minutes to separate the plasma. The obtained plasma sample was stored at -40 to -20°C for biological sample analysis.

[0442] Pharmacokinetic parameters

[0443] After detecting blood drug concentrations by LC-MS / MS analysis, the corresponding pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 8.3. The mouse pharmacokinetic parameters of the compounds of this invention are as follows:

[0444]

[0445] Conclusion: The compounds of this invention are well absorbed orally in mice and exhibit excellent pharmacokinetic characteristics.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: key express It can exist as a (Z)- or (E)- stereoisomer, where -* indicates a connection point; X is selected from CR a Or N; Y is selected from CR b Or N; Z is selected from CR c Or N; R a Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 Substituents of alkoxy groups; R b Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; R c Selected from hydrogen atoms, C 1-6 Alkyl, -NR 6 R 7 or -N(R) 6 )C(=O)R 7 ; W is selected from O or NR e ; R e Selected from hydrogen atom, deuterium atom, cyano group, C 1-6 Alkyl, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 6-10 The aryl or 5-6 heteroaryl group may be further selected from one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R 4 Selected from -OR 5 -NR 6 R 7 3-10 membered heterocyclic groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl; wherein the 3-10 membered heterocyclic group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R 1 Selected from hydrogen atoms, C 3-8 cycloalkyl, -OR A Or S(O) r R A The C mentioned therein 3-8 The cycloalkyl group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced; R A Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups may be further substituted with one or more R groups. AA replace R AA Selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl, 5-6 heteroaryl, =O, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, two Rs AA Together with the same carbon atom it is attached to, it forms a -C (=O); Or, two Rs AA Together with the same carbon atom it is attached to, they form a C 3-8 Cycloalkyl or 3-10 membered heterocyclic group; wherein the C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups may be selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; R 2 Selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, R 2 and X, R 2 Each of Y and its bonded atoms independently forms a 5-6 aryl or heteroaryl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; R d Selected from hydrogen atoms, C 1-6 Alkyl or C 0-6 Alkylene-R B ; R B Selected from hydroxyl, alkenyl, alkynyl, cyano, C 3-12 cycloalkyl, C 6-10 aryl, 3-12 heterocyclic, 5-10 membered heteroaryl, or 8-10 membered fused ring, wherein the alkenyl, alkynyl, C 3-12 cycloalkyl, C 6-10 Aryl, 3-12 heterocyclic, 5-10 heteroaryl, or 8-10 fused ring may be further coupled with one or more R C Replaced; R C Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 quinone heteroaryl, optionally further substituted by one or more R D Replaced; Or, two Rs C Together with the same carbon atom it is attached to, it forms a -C (=O); R D Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, two Rs D Together with the same carbon atom it is attached to, it forms a -C (=O); R f Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-10-membered heterocyclic groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R g Each atom is independently selected from hydrogen atoms or deuterium atoms, preferably hydrogen atoms; R 3a R 3b Each is independently selected from hydrogen atoms, deuterium atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group; wherein the C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, or C. 1-6 Substituents of alkoxy groups; The condition is that when W is 0, and R... 4 C is an optional replacement 1-6 Alkyl or optionally substituted C 3-8 When cycloalkyl, R 3a R 3b They are not both hydrogen atoms; R 5 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups may be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 6 and R 7 Each is independently selected from hydrogen atoms, hydroxyl groups, and C atoms. 1-6 Alkyl, C 3-8 cycloalkyl, 3-10 heterocyclic, C 6-10 Aryl or 5-6 quinone heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-6 heteroaryl groups may be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Substituted by aryl, 5-6 heteroaryl, carboxyl or carboxylic acid ester groups; r can be 0, 1, or 2 independently; Formula (I) does not contain the following compounds:

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein W is selected from O; R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; and R 3a R 3b They are not both hydrogen atoms; R 4 Selected from C 1-6 Alkyl or C 3-8 cycloalkyl, wherein the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein: R 3a It is a hydrogen atom; R 3b Selected from deuterium atoms, halogens, cyano groups, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl.

4. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein: R 3b It is a hydrogen atom; R 3a Selected from deuterium atoms, halogens, cyano groups, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl.

5. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein: W is selected from O; R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; preferably, R 3a R 3b It is a hydrogen atom; R 4 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, -OR 5 -NR 6 R 7 Or a 3-10 member heterocyclic group, wherein the C 2-6 alkenyl, C 2-6 The alkynyl or 3-10 membered heterocyclic group may optionally be further selected from one or more deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl.

6. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein W is selected from NR. e R e Selected from hydrogen atom, deuterium atom, or C atom 1-6 Alkyl, preferably, the R e Selected from hydrogen atoms or C 1-6 Alkyl, more preferably, the C 1-6 The alkyl group is methyl; R 3a R 3b Each is independently selected from hydrogen atom, deuterium atom, halogen, cyano group or C. 1-6 Alkyl; wherein the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano or C. 1-6 The alkoxy group is substituted; preferably, R 3a R 3b It is a hydrogen atom; R 4 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be further selected from one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R d It is a hydrogen atom.

8. The compound according to any one of claims 1-7, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R f Selected from C 3-8 Cycloalkyl, preferably cyclopropyl.

9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OR A , R A Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-10 membered heterocyclic or C 6-10 Aryl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group is optionally further modified by an R AA replace; R AA Selected from C 3-8 cycloalkyl; Or, two Rs AA Together with the same carbon atom it is attached to, they form a C 3-8 Cycloalkyl.

10. The compound according to claim 9, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R A Selected from the following groups:

11. The compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein Z is selected from CR. c Or N, R c It is a hydrogen atom.

12. The compound according to any one of claims 1-11, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein X is selected from CR a Or N, R a It is a hydrogen atom.

13. The compound according to any one of claims 1-12, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein Y is selected from CR. b Or N, R b Selected from hydrogen atom, halogen, deuterium atom, nitro group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OR 5 -NR 6 R 7 -C(=O)R 5 -S (=O) r R 5 3-10 heterocyclic group, C 3-8 cycloalkyl, 5-6-membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 heterocyclic, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkyl halogenates are substituted. R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl; r is 2.

14. The compound according to claim 13, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R b Selected from the following groups: hydrogen atom, deuterium atom, fluorine, chlorine, bromine, hydroxyl, methoxy, amino, dimethylamino, vinyl, ethynyl.

15. The compound according to any one of claims 1-14, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from SF5, hydroxyl, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further replaced by one or more halogens.

16. The compound of claim 15 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein R 2 Selected from SF5 or 17. The compound according to any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is:

18. A pharmaceutical composition comprising an effective dose of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1-17, and a pharmaceutically acceptable carrier, excipient or combination thereof.

19. Use of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a WRN inhibitor.

20. Use of the compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating WRN-mediated diseases; preferably, wherein the WRN-mediated disease is a highly microsatellite unstable cancer; more preferably, the highly microsatellite unstable cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct carcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia, or glioma, and even more preferably colorectal cancer, gastric cancer, or endometrial cancer.

21. The use of the compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating highly microsatellite unstable cancers; preferably, wherein the highly microsatellite unstable cancers are selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia, or glioma, more preferably colorectal cancer, gastric cancer, or endometrial cancer.

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