Nitrogen-containing compound for inhibiting WRN helicase, pharmaceutical composition containing same, and use thereof

Abstract

Provided in the present invention are a nitrogen-containing compound for inhibiting WRN helicase, a pharmaceutical composition containing same, and a use thereof. Specifically, provided in the present invention are a compound shown in formula (I), a stereoisomer thereof, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a crystal form thereof, an isotopic derivative thereof, a prodrug thereof, a metabolite thereof, and a solvate or a hydrate thereof. Also provided are a composition containing the compound and the use thereof as a WRN helicase inhibitor in the prevention or treatment of related diseases.

Description

A nitrogen-containing compound that inhibits WRN helicase, a pharmaceutical composition containing the compound, and their applications. Technical Field

[0001] This disclosure relates to nitrogen-containing compounds or pharmaceutically acceptable salts thereof, methods of their preparation, pharmaceutical compositions containing them, and their use as WRN inhibitors in the prevention or treatment of related diseases. Background Technology

[0002] Microsatellite instability (MSI-H) is a genetic characteristic of certain cancers, characterized by abnormal duplication and amplification of microsatellite regions in DNA. MSI-H is associated with a variety of cancers, including colorectal cancer, gastric cancer, and endometrial cancer. MSI-H tumor cells exhibit genomic instability and generate numerous mutations due to defects in DNA repair mechanisms. Immune checkpoint inhibitors (CPIs) have become an important treatment for MSI-H tumors; however, not all patients respond to CPIs, and some may experience treatment resistance and disease progression due to tumor heterogeneity, altered immune microenvironment, and other factors. Therefore, new treatment methods are needed for MSI-H tumors.

[0003] WRN helicase is a RecQ-like helicase that plays a crucial role in the growth of MSI-H tumor cells. Studies have shown that the absence or loss of function of WRN helicase triggers a "synthetic lethality" effect in MSI-H tumor cells, i.e., cell death. WRN holds promise as a novel therapeutic target for MSI-H tumors. Given the significant unmet clinical need, the development of small molecule inhibitors of WRN has broad application prospects. Summary of the Invention

[0004] This invention provides a biheterocyclic derivative that inhibits WRN helicase, a pharmaceutical composition containing the derivative, and its application.

[0005] In a first aspect, the present invention provides a compound of formula (I), its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates, or its hydrates.

[0006] Where X is selected from O, S, Se, CR8, N, or NR9; Y is selected from O, S, CR 10 , N, or NR 11 The premise is It has aromatic properties;

[0007] R8, R9, R 10 and R 11 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1-4Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0008] R1 is selected from the following group:

[0009] (1)C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, C 6-12 Aryl, C 2-6 Alkenyl, 4-6 membered heterocyclic, 5-12 heteroaryl; the above groups are optionally surrounded by 1, 2 or 3 R groups. 1a And 1, 2 or 3 R 1b Replace; R 1a Optionally by 1, 2 or 3 R 1a-1 Replace; R 1b Optionally by 1, 2 or 3 R 1b-1 replace;

[0010] R 1a and R 1b Each group is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, carboxyl, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 alkylamine group, C 6-12 aryl, 5-12 heteroaryl; or R 1a R 1b Together with the atoms they are attached to, they form C 3-6 A carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered heterocycle contains 1, 2, or 3 heteroatoms selected from O, N, and S, wherein R 1a and R 1b They can be located on the same or different atoms; the above C 3-6 The carbon ring or 3-6 membered heterocycle is optionally surrounded by 1, 2 or 3 Rs 1creplace;

[0011] Each R 1c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0012] R 1a-1 and R 1b-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 6-acetylinyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0013] (2)-NR 1e R 1d ;

[0014] R 1e and R 1d Each of them independently selected from the following group: C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1e Optionally by 1, 2 or 3 R 1e-1 Replace; R 1d Optionally by 1, 2 or 3 R 1d-1 Replace; or R 1e R 1dTogether with the N atoms they are attached to, they form 3-8 membered heterocycles, wherein the 3-8 membered heterocycles contain 1, 2, or 3 heteroatoms selected from O, N, and S; the 3-8 membered heterocycles are optionally separated by 1, 2, or 3 R atoms. 1g replace;

[0015] Each R 1g Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; or two R groups 1g They can together form C 3-6 Carbon rings or 3-6 membered heterocycles, with two Rs 1g They can be located on the same or different ring atoms;

[0016] R 1e-1 and R 1d-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 6-acetylinyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0017] (3)-SR 1j ;

[0018] R 1j Selected from the following group: C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1j Optionally by 1, 2 or 3 R 1k replace;

[0019] Each R 1kIndependently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0020] (4)-OR 1m ;

[0021] R 1m Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1m Optionally by 1, 2 or 3 R 1n replace;

[0022] Each R 1n Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; R2 is -OR 12 or -SR 12 , where R 12 Selected from the following group: C 3-8 cycloalkyl, C 1-6 Alkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic; R 12 The land can be optionally divided by 1, 2, 3, 4, 5 or 6 Rs. 12a Replace; R 12a Choose any 0, 1, 2 or 3 Rs 12a-1 replace;

[0023] Each R 12a and R 12a-1Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0024] W is:

[0025] * indicates the location connected to the parent core;

[0026] R3 is selected from the following groups: H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl; R3 is optionally surrounded by 1, 2 or 3 Rs 3a replace;

[0027] Each R 3a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0028] R4 is selected from the following groups: H, D, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl; R4 optionally surrounded by 1, 2 or 3 Rs 4b replace;

[0029] Each R 4b Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 1-6 alkenyl, C 1-6 Haloalkenyl, C 1-6 Alkylamine group;

[0030] R 4a -C 0-4 Alkylene-R 4a-1 , where R 4a-1 Selected from the following group: C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkenyl, 5-6 membered heterocyclic, 5-6 membered aromatic heterocyclic, phenyl, 3-12 membered biheterocyclic; R 4a Optionally by 1, 2 or 3 R 4c replace;

[0031] Each R 4c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 alkylamine group, C 6-10 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic;

[0032] R5 is selected from H and D;

[0033] R6 is selected from H, D, halogen, or cyano;

[0034] R7 is selected from the following group: C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered oxocyclic, 3-8 membered nitrogen-containing heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; R7 optionally covered with 1, 2 or 3 Rs 7a replace;

[0035] Each R 7a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6alkynyl group, C 1-6 alkenyl, C 1-6 Haloalkenyl, C 1-6 Alkylamine group;

[0036] Or, R7, R 4a Together with the atoms they are attached to, they form C 7-15 A carbon ring or a 7-15 membered heterocycle, wherein the formed 7-15 membered heterocycle contains 1-7 heteroatoms selected from O, S, or N; the formed C 7-15 The carbon ring or 7-15 membered heterocycle is optionally surrounded by 1, 2, 3, 4 or 5 R... 7b replace;

[0037] Each R 7b Independently selected from the following groups: H, D, halogen, cyano, amino, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0038] Each R 7c Independently selected from the following groups: H, cyano, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Halogenated alkyl groups.

[0039] In a preferred embodiment, R1 is selected from the group consisting of:

[0040] (1)C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, phenyl, naphthyl, C 2-4 alkenyl, 4-6 membered heterocyclic, 5-9 heteroaryl; the above groups are optionally surrounded by 1, 2 or 3 R groups. 1a And 1, 2 or 3 R 1b Replace; R 1a Optionally by 1, 2 or 3 R 1a-1 Replace; R 1b Optionally by 1, 2 or 3 R 1b-1 replace;

[0041] R 1a and R 1bEach is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 alkylamine group, C 6-12 aryl, 5-9 quinone heteroaryl; or R 1a R 1b Together with the atoms they are attached to, they form C 3-6 A carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered heterocycle contains 1, 2, or 3 heteroatoms selected from O, N, and S, wherein R 1a and R 1b They can be located on the same or different atoms; the above C 3-6 The carbon ring or 3-6 membered heterocycle is optionally surrounded by 1, 2 or 3 Rs 1c replace;

[0042] Each R 1c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0043] R 1a-1 and R 1b-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 4-Alynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0044] (2)-NR 1e R 1d ;

[0045] R 1e and R 1d Each of them independently selected from the following group: C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2-4 alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1e Optionally by 1, 2 or 3 R 1e-1 Replace; R 1d Optionally by 1, 2 or 3 R 1d- 1 replaces; or R 1e R 1d Together with the N atoms they are attached to, they form 3-6 membered heterocycles, wherein the 3-8 membered heterocycles contain 1, 2, or 3 heteroatoms selected from O, N, and S; the aforementioned 3-6 membered heterocycles are optionally separated by 1, 2, or 3 R atoms. 1g replace;

[0046] Each R 1g Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-6 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; or two R groups 1g They can together form C 3-6 Carbon rings or 3-6 membered heterocycles, with two Rs 1g They can be located on the same or different ring atoms;

[0047] R 1e-1 and R 1d-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 4-Alynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0048] (3)-SR 1j ;

[0049] R 1j Selected from the following group: C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2-4 alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1j Optionally by 1, 2 or 3 R 1k replace;

[0050] Each R 1k Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0051] (4)-OR 1m ;

[0052] R 1m Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2- 4-Alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1m Optionally by 1, 2 or 3 R 1n replace;

[0053] Each R 1n Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0054] Preferably, R1 is selected from the group consisting of:

[0055] * indicates the location of the link key, which is connected to the mother core.

[0056] In a preferred embodiment, R3 is selected from the group consisting of: H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl.

[0057] In a preferred embodiment, the R 4a -C 0-2 Alkylene-R 4a-1 , where R 4a-1 Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkenyl, 5-6 membered heterocyclic group, 5-6 membered aromatic heterocyclic group, phenyl, 6-10 membered biheterocyclic group;

[0058] Preferably, the R 4a Selected from the following group:

[0059] * indicates the location of the link key, which is connected to the mother core.

[0060] In a preferred embodiment, R7 is selected from the group C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl, 3-6 membered oxoheterocyclic, 3-6 membered nitrogen-heterocyclic.

[0061] In a preferred embodiment, R2 is -OR 12 , where R 12 Selected from the following group: C 3-6 cycloalkyl, C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic; R 12 The land can be optionally divided by 1, 2, 3, 4, 5 or 6 Rs. 12a replace;

[0062] Each R 12a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group;

[0063] Preferably, R2 is selected from the group consisting of:

[0064] * indicates connection to the parent nucleus.

[0065] In another preferred embodiment, R2 is selected from the group consisting of:

[0066] (1)-O-(optionally substituted C) 3-8 cycloalkyl) optional substituted C 3-8 Cycloalkyl groups can be denoted by 0-6 R groups. 2a Replace; R 2a You can choose any 0, 1, 2 or 3 Rs. 2a-1 Replace; R 2a and R 2a-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0067] (2)-O-(optionally substituted C) 1-6 Alkyl), optionally substituted C 1-6 Alkyl groups can be 0-6 R 2b Replace; R 2b You can choose any 0, 1, 2 or 3 Rs. 2b-1 Replace; R 2b and R 2b-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0068] (3)-O-(optionally substituted C) 6-10 aryl), optionally substituted C 6-10 Aryl groups can be substituted by 0-6 R groups. 2c Replace; R 2c You can choose any 0, 1, 2 or 3 Rs. 2c-1 Replace; R 2c and R 2c-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0069] (4)-O-(optionally substituted 5-6 heteroaryl), the optionally substituted 5-6 heteroaryl can be substituted by 0-6 R 2d Replace; R 2d You can choose any 0, 1, 2 or 3 Rs. 2d-1 Replace; R 2d and R 2d-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group;

[0070] (5)-O-(optionally substituted 5-6 membered heterocyclic group), the optionally substituted 5-6 membered heterocyclic group can be substituted by 0-6 R 2e Replace; R2e You can choose any 0, 1, 2 or 3 Rs. 2e-1 Replace; R 2e and R 2e-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group.

[0071] In a preferred embodiment, the compound has the structure shown in formula (I-1), (I-2), or (I-3):

[0072] The definitions of R1, R2, R9, and W are as described above.

[0073] In another preferred embodiment, the compound has the structure shown in formula (I-4).

[0074] Among them, X, R1, R 12 R3, R 4a The definitions of R4, R5, R6 and R7 are as described above.

[0075] In a preferred embodiment, the compound is selected from the group consisting of:

[0076] A second aspect of the present invention provides a pharmaceutical composition comprising a compound as described in the first aspect of the present invention, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate; and a pharmaceutically acceptable carrier.

[0077] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0078] In another preferred embodiment, the other therapeutic agent is a chemotherapy drug, an immunotherapy drug, or a targeted drug.

[0079] In another preferred embodiment, the chemotherapeutic drugs are selected from: anastrozole, bicalutamide, bleomycin sulfate, busulfan, busulfan injection, capecitabine, N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, cytarabine liposome injection, dacarbazine, actinomycin, daunorubicin hydrochloride, daunorubicin citrate liposome injection, dexamethasone, docetaxel, doxorubicin hydrochloride, and etoposide. Fludarabine phosphate, 5-fluorouracil, flutamide, tezacitamine, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, gemtuzumab, paclitaxel, pentostatin, tamoxifen citrate, teniposide, 6-thioguanine, thiotepa, terazamine, topotecan hydrochloride for injection, vinblastine, vincristine, and vinorelbine; preferably 5-fluorouracil (5-FU) and irinotecan.

[0080] In another preferred embodiment, the immunotherapy drug is selected from: PD-1 inhibitors (including small molecule and antibody drugs), PD-L1 inhibitors (including small molecule and antibody drugs), CTLA-4 inhibitors, PD-1 / CTLA-4 bispecific antibodies, PD-1 / TIGIT bispecific antibodies, PD-L1 / 4-1BB bispecific antibodies, PD-1 / VEGF-A bispecific antibodies, and PD-1 / LAG-3 bispecific antibodies;

[0081] Among them, the PD-1 inhibitors are selected from: nivolumab, pembrolizumab, camrelizumab, toripalimab, sintilimab, tislelizumab, penaprilimab, cepalimumab, slulimab, dostarlimab and PDR001;

[0082] Among them, the PD-L1 inhibitors are selected from: durvalumab, atezolizumab, envorimab, and sugemalimab;

[0083] Among them, the CTLA-4 inhibitor was selected from ipilimumab;

[0084] Among them, the PD-1 / CTLA-4 bispecific antibody was selected from catuninirimumab.

[0085] In another preferred embodiment, the targeted drug includes, but is not limited to, VEGFR inhibitors (lenvatinib), NTRK inhibitors (entrectinib), BRAFV600 inhibitors (dabrafenib), MEK inhibitors (trametinib), EGFR monoclonal antibodies (cetuximab), PARP inhibitors (olaparib, niraparib, fluzoparib, and pamiparib, etc.) and ATR inhibitors.

[0086] A third aspect of the present invention provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the present invention, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotope derivative, its prodrug, its metabolite, its solvate, or its hydrate thereof, thereby forming a pharmaceutical composition as described in the second aspect of the present invention.

[0087] A fourth aspect of the present invention provides the use of a compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate or hydrate thereof, or a pharmaceutical composition as described in the first aspect of the present invention, in the preparation of a medicament for treating WRN helicase-mediated diseases.

[0088] In another preferred embodiment, the disease is a tumor.

[0089] In another preferred embodiment, the disease is a microsatellite unstable tumor.

[0090] In another preferred embodiment, the tumor is characterized by high microsatellite instability (MSI-H) or by defective mismatch repair (dMMR) or “dMMR features”.

[0091] Among them, the microsatellite unstable tumors include, but are not limited to, uterine fibroids, endometrial cancer, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cyst carcinoma.

[0092] Tumors with "defective mismatch repair" (dMMR) or "dMMR features" include, but are not limited to, lung cancer, breast cancer, kidney cancer, colorectal cancer, ovarian cancer, prostate cancer, upper respiratory and digestive tract cancer, gastric cancer, endometrial cancer, liver cancer, pancreatic cancer, hematopoietic and lymphatic tissue cancer, skin cancer, thyroid cancer, pleural cancer, autonomic nervous system tumors, soft tissue tumors, rhabdomyosarcoma, melanoma, and other tumors.

[0093] In another preferred embodiment, the drug is administered orally, by injection, inhalation, or via a cavity.

[0094] In another preferred embodiment, the dosage form of the drug is selected from: tablets, capsules, dispersants, suspensions, granules, sprays, gels, sustained-release agents, oral liquids, pellets, and nanoformulations.

[0095] In a fifth aspect, the present invention provides a method for treating WRN helicase-mediated diseases, comprising the steps of administering to a subject requiring treatment an effective amount of a compound, stereoisomer thereof, optical isomer thereof, pharmaceutically acceptable salt thereof, crystal form thereof, isotopic derivative thereof, prodrug thereof, metabolite thereof, solvate thereof or hydrate thereof, or pharmaceutical composition as described in the second aspect.

[0096] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0097] Through extensive and in-depth research, the inventors discovered for the first time a nitrogen-containing heterocyclic derivative with a novel structure and good WRN helicase inhibitory activity. Based on this, the inventors completed this invention.

[0098] the term

[0099] Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below.

[0100] "Alkyl" (alone or as part of other groups) refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms. Among them, "C..." 1-6 "Alkyl" refers to an alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms. "C" 1-4 "Alkyl" refers to an alkyl group containing 1, 2, 3, or 4 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc.

[0101] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds ("C"). 2-6 ("alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 (Alkenyl). One or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2–6 Examples of alkenyl groups include the C group mentioned above. 2–4 Alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc.

[0102] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds ("C"). 2-6 (Alkyne group).

[0103] “C 1-4 "Deuterated alkyl" (alone or as part of other groups) refers to an alkyl group containing 1, 2, 3, or 4 carbon atoms that has been replaced by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deuterium atoms. Examples of deuterated alkyl groups include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0104] "Alkoxy" (alone or as part of other groups) refers to the -OR group, where R is an alkyl group as defined herein. C 1-4 Alkoxy groups refer to alkoxy groups containing 1, 2, 3, or 4 carbon atoms. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0105] "Halogen (halogenated)" (alone or as part of other groups) refers to fluorine, chlorine, bromine or iodine.

[0106] "Halogenated alkyl" (alone or as part of other groups) refers to the group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. Wherein, "C..." 1-4 "Halogenated alkyl" refers to an alkyl halogroup containing 1, 2, 3, or 4 carbon atoms. Examples of alkyl halogroups include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3-, -CF2CF3), etc.

[0107] "Haloalkoxy" (alone or as part of other groups) refers to a group of formula -OR, where R is a haloalkyl group as defined herein. "C" 1-4 "Haloalkoxy" refers to an alkoxy group containing 1, 2, 3, or 4 carbon atoms that are substituted with multiple halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and 2,2,2-trifluoroethoxy.

[0108] "Cycloalkyl" (alone or as part of other groups) refers to a monovalent saturated carbocyclic group consisting of only carbon and hydrogen atoms in a single or bicyclic ring. 3-8"Cycloalkyl" refers to a saturated carbocyclic group containing 3 to 8 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may optionally be substituted by one or more substituents, wherein each substituent is independently a hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0109] "Cycloalkoxy" (alone or as part of other groups) refers to the formula -OR group, where R is a cycloalkyl group as defined herein. "C 3-8 "Cycloalkoxy" refers to a saturated carbon epoxy group containing 3 to 8 carbon atoms. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0110] A "heterocyclic group" (alone or as part of another group) refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic systems), wherein at least one heteroatom selected from N, O, or S is present in a ring with at least one carbon atom. Each heterocycle containing a heteroatom has 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur atom may be oxidized or quaternized. Heterocyclic alkane(group) refers to a fully saturated heterocycle(group). Heterocyclic groups can be attached to any heteroatom or carbon residue in a ring or cyclic molecule. "3-6 membered heterocyclic group" refers to a group having 3, 4, 5, or 6 ring members. "3-4 membered heterocyclic group" refers to a group having 3 or 4 ring members. Typical monocyclic heterocyclic compounds include, but are not limited to: nitrogen-containing heterocyclic butyl groups, pyrrolyl groups, oxocyclic butyl groups, pyrazolinyl groups, imidazolinyl groups, imidazoalkyl groups, oxazolinyl groups, isoxazolinyl groups, thiazoalkyl groups, isothiazolinyl groups, tetrahydrofuranyl groups, piperidinyl groups, piperazinyl groups, 2-oxopiperidinyl groups, 2-oxopiperidinyl groups, 2-oxopiperylyl groups, hexahydroachenginyl groups, 4-piperidinoneyl groups, tetrahydropyranyl groups, morpholinyl groups, thiomorpholinyl groups, thiomorpholinyl sulfoxide groups, thiomorpholinyl sulfone groups, 1,3-dioxylyl groups, and tetrahydro-1,1-dioxothiophene groups, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0111] "Aryl" (alone or as part of other groups) refers to an aromatic cyclic hydrocarbon compound group having 1-5 rings, especially monocyclic and bicyclic groups. Any compound containing two or more aromatic rings (bicyclic, etc.) can have these rings linked by single bonds (e.g., biphenyl) or fused together (e.g., naphthalene, anthracene, etc.). Among these, "C..." 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through a single bond or any two adjacent ring carbon atoms, such as benzotetrahydrofuranyl, benzotetrahydropyranyl, and benzodioxaneyl. wait.

[0112] "Heteroaryl" (alone or as part of other groups) refers to an aromatic group whose skeleton has heteroatoms. "5-12 membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic group with 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, containing at least one (e.g., 1, 2, or 3) ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C aromatic rings. It should be clearly understood that the connection point of the heteroaryl group should be located on the aromatic ring. Preferably, the heteroaryl group has 5-8 ring atoms (5-8 members), more preferably 5-6 ring atoms (5-6 members). Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzimidazole, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide acridine group, etc.

[0113] Cycloalkenyl groups (alone or as part of other groups) refer to groups whose skeletal portion contains a carbon-carbon double bond, either a carbon ring or a heterocycle; where "C" is the carbon ring. 3-8 "Cycloalkenyl" refers to a monocyclic, bicyclic, or tricyclic group with 3, 4, 5, 6, 7, or 8 ring atoms, including fused, spirocyclic, and bridged rings; it contains at least one (e.g., 1, 2, or 3) carbon-carbon double bond; cycloalkenyl groups containing heteroatoms contain at least one (e.g., 1, 2, or 3) heteroatom selected from N, O, or S; it should be clear that the cycloalkenyl group should be attached to a carbon-carbon double bond.

[0114] “C 3-8"Heterocyclic alkenyl" refers to a monocyclic, bicyclic, or tricyclic group with 3, 4, 5, 6, 7, or 8 ring atoms, including fused, spirocyclic, and bridged rings; it contains at least one (e.g., 1, 2, or 3) carbon-carbon double bond; and at least one (e.g., 1, 2, or 3) heteroatom selected from N, O, or S; it should be clear that the cycloalkenyl group should be attached to the carbon-carbon double bond.

[0115] "3-12 membered heterocycles" refer to non-aromatic rings consisting of 3 to 12 members (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 members) having a ring carbon atom and 1, 2, 3, 4, or 5 cyclic heteroatoms. These include monocyclic, bicyclic, tricyclic, and tetracyclic rings, which can form bicyclic, tricyclic, and tetracyclic rings through fusion and spirolysis. Each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocycles containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 3-6 membered heterocycle is preferred, which is a 3- to 6-membered (3, 4, 5, or 6-membered) non-aromatic ring system having a cyclic carbon atom and 1, 2, or 3 cyclic heteroatoms; in some embodiments, a 4- to 6 membered heterocycle is preferred, which is a 4- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, a 5- to 6 membered heterocycle is preferred, which is a 5- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; exemplary 3-membered heterocycles containing one heteroatom include, but are not limited to: azirropropane, oxacyclopropane, and thioheteropropane. Exemplary 4-membered heterocycles containing one heteroatom include, but are not limited to: azirrobutane, oxacyclobutane, and thioheterobutane. Exemplary 5-membered heterocycles containing one heteroatom include, but are not limited to: tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrole, dihydropyrrole, and pyrrole-2,5-dione. Exemplary 5-membered heterocycles containing two heteroatoms include, but are not limited to: dioxacyclopentane, oxothiacyclopentane, dithiacyclopentane, and oxazolidin-2-one. Exemplary 5-membered heterocycles containing three heteroatoms include, but are not limited to: triazoline, oxadiazoline, and thiadiazoline. Exemplary 6-membered heterocycles containing one heteroatom include, but are not limited to: piperidine, tetrahydrofuran, dihydropyridine, and thiacyclohexane. Exemplary 6-membered heterocycles containing two heteroatoms include, but are not limited to: piperazine, morpholino, dithiacyclohexane, and dioxane. Exemplary 6-membered heterocycles containing three heteroatoms include, but are not limited to: hexahydrotriazine. Exemplary 7-membered heterocycles containing one heteroatom include, but are not limited to: azirheptanane, oxacycloheptanane, and thiacycloheptanane.

[0116] "3-12 membered biheterocyclic group" refers to a 3 to 12 membered (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered) non-aromatic bicycle with a cyclic carbon atom and 1, 2, 3, 4 or 5 cyclic heteroatoms. It can be a fused ring, a bridged ring or a spirocycle.

[0117] "5-6 membered heteroaromatic ring" refers to a 4n+2 aromatic ring system having a 5-6 membered monocyclic ring with 1, 2, 3, or 4 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided the valence allows. Heteroaromatic rings also include ring systems in which the aforementioned heteroaromatic ring is fused with one or more cycloalkanes or heterocycles, and the linkage is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaromatic ring system. In some embodiments, a 5-6 membered heteroaromatic ring is a 4n+2 aromatic ring system having a 5-6 membered monocyclic ring with 1-4 heteroatoms. Exemplary 5-membered heteroaromatic rings containing one heteroatom include, but are not limited to: pyrrole, furan, and thiophene. Exemplary 5-membered heteroaromatic rings containing two heteroatoms include, but are not limited to: imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole. Exemplary 5-membered heteroaryl rings containing three heteroatoms include, but are not limited to: triazoles, oxadiazoles, and thiadiazoles. Exemplary 5-membered heteroaryl rings containing four heteroatoms include, but are not limited to: tetrazolium. Exemplary 6-membered heteroaryl rings containing one heteroatom include, but are not limited to: pyridine. Exemplary 6-membered heteroaryl rings containing two heteroatoms include, but are not limited to: pyridazines, pyrimidines, and pyrazines. Exemplary 6-membered heteroaryl rings containing three or four heteroatoms include, but are not limited to: triazines and tetraazines, respectively.

[0118] “C 1-6 "Alkylamine group" refers to the H in NH2 being surrounded by one or two C groups. 1-4 Alkyl, C 3-6 The total number of carbon atoms in the groups obtained by cycloalkyl substitution does not exceed 6.

[0119] “C 3-6 A "carbon ring" is a monocyclic saturated carbon ring with 3, 4, 5, or 6 ring carbon atoms. Examples of 3–6 membered carbon rings include the aforementioned 5–6 membered cycloalkanes, as well as cyclopropyl and cyclobutyl groups.

[0120] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, and the substituents are, for example (but not limited to): halogen, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0121] As used in this article, the term "multiple substitutions" refers to 2, 3, 4, 5, or 6 substitutions.

[0122] As used in this article, the term "one or more" refers to 1, 2, 3, 4, 5, or 6.

[0123] Active ingredients

[0124] As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0125] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0126] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that allows for free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0127] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography. See, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'SENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0128] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0129] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P,32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0130] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0131] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0132] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0133] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0134] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0135] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0136] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0137] Pharmaceutical Compositions and Administration

[0138] Because the compounds of the present invention can inhibit WRN helicase and are used to treat diseases such as tumors, the compounds of the present invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) WRN helicase-related diseases, preferably tumors; more preferably, microsatellite unstable tumors; and even more preferably, tumors characterized by high microsatellite instability (MSI-H) or having "defective mismatch repair deficiency (dMMR)" or "dMMR characteristics".

[0139] Microsatellite unstable tumors are particularly prevalent in colorectal cancer, gastric cancer, and endometrial cancer, but are also found in adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer, and ovarian cancer. Microsatellite unstable tumors include, but are not limited to, uterine fibroids, endometrial cancer, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystic carcinoma.

[0140] Tumors with “defective mismatch repair” (dMMR) or “dMMR features” include cancer-type mechanisms associated with recorded mutations or epigenetic silencing of MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1, microsatellite vulnerable sites, or other gene inactivation, including but not limited to lung cancer, breast cancer, kidney cancer, colorectal cancer, ovarian cancer, prostate cancer, upper respiratory and digestive tract cancers, gastric cancer, endometrial cancer, liver cancer, pancreatic cancer, hematopoietic and lymphoid tissue cancers, skin cancer, thyroid cancer, pleural cancer, autonomic nervous system tumors, soft tissue tumors, rhabdomyosarcoma, melanoma, and other tumors.

[0141] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0142] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0143] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0144] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0145] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0146] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0147] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0148] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0149] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0150] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. Drugs administered in combination with WRN inhibitors include, but are not limited to, chemotherapeutic agents, immunotherapeutic agents, and targeted therapies. When administered in combination, the pharmaceutical composition further includes one or more (two, three, four, or more) other pharmaceutically acceptable therapeutic agents. One or more (two, three, four, or more) of these other pharmaceutically acceptable therapeutic agents can simultaneously treat microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) tumors with the compounds of this invention.

[0151] Chemotherapy drugs

[0152] Chemotherapy drugs include, but are not limited to, 5-fluorouracil (5-FU), irinotecan, anastrozole, bicalutamide, bleomycin sulfate, busulfan, busulfan injection, capecitabine, N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, cytarabine liposome injection, dacarbazine, actinomycin, daunorubicin hydrochloride, daunorubicin citrate, liposome injection, and dexamethasone. Docetaxel, Doxorubicin Hydrochloride, Etoposide, Fludarabine Phosphate, 5-Fluorouracil, Flutamide, Tezacitamine, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, L-Asparaginase, Leucovorin, Melphalan, 6-Mercaptopurine, Methotrexate, Mitoxantrone, Gelatumab, Paclitaxel, Pentostatin, Tamoxifen Citrate, Teniposide, 6-Thioguanine, Thiotepa, Tirazamine, Topotecan Hydrochloride for Injection, Vincristine, Vincristine, and Vinorelbine.

[0153] Immunotherapy drugs

[0154] Immunotherapy drugs include, but are not limited to, PD-1 inhibitors (including small molecule and antibody drugs), PD-L1 inhibitors (including small molecule and antibody drugs), CTLA-4 inhibitors, PD-1 / CTLA-4 bispecific antibodies, PD-1 / TIGIT bispecific antibodies, PD-L1 / 4-1BB bispecific antibodies, PD-1 / VEGF-A bispecific antibodies, PD-1 / LAG-3 bispecific antibodies, and other immunotherapy drugs.

[0155] Targeted drugs

[0156] Targeted therapies include, but are not limited to, VEGFR inhibitors (lenvatinib), NTRK inhibitors (entrectinib), BRAFV600 inhibitors (dabrafenib), MEK inhibitors (trametinib), EGFR monoclonal antibodies (cetuximab), PARP inhibitors (olaparib, niraparib, fluzoparib, and pamiparib, etc.) and ATR inhibitors.

[0157] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0158] The present invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods not specifically described in the following embodiments are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. The compounds of the present invention have their structures determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are in units of 10-1. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0159] The abbreviations for this invention are defined as follows:

[0160] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0161] DMSO: Dimethyl sulfoxide; NMP: N-methylpyrrolidone; DMAP: 4-dimethylaminopyridine; DCC: N,N'-dicyclohexylcarbodiimide; BAST: bis(2-methoxyethyl)aminosulfur trifluoride; DAST: diethylaminosulfur trifluoride; DIEA: N,N-diisopropylethylamine; DCM: dichloromethane; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; HATU: 2- (7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; T3P: 1-Propylphosphine; DMP: (1,1,1-Triacetoxy)-1,1-Dihydro-1,2-Benziodo-3(1H)-one; PTAS: p-Toluenesulfonic acid; DIBAL-H: Diisobutylaluminum hydride; PE: Petroleum ether; EA: Ethyl acetate; m-CPBA: m-chloroperoxybenzoic acid; TEA: Triethylamine

[0162] IC 50 The half-maximum inhibitory concentration (MCI) is the concentration at which half of the maximum inhibitory effect is achieved.

[0163] Unless otherwise instructed, the preparative liquid chromatography separation conditions are as follows: Preparative column: Agilent 10Prep–C18250*21.2mm, Mobile phase A: 0.1% ammonia in H2O, Mobile phase B: acetonitrile, 45%–55% acetonitrile, 30 mL / min

[0164] Intermediate 30a: Ethyl 4-chloro-2-(1,1-difluoro-3-methoxypropyl)thiazole-5-carboxylate

[0165] Step 1 N,3-Dimethoxy-N-methylpropionamide 30a-2

[0166] Compound 30a-1 (5 g, 48.07 mol) was dissolved in DMF (50 mL), and N,O-dimethylhydroxylamine hydrochloride (6.9 g, 72.1 mol), DIEA (31 g, 240.3 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (20.1 g, 52.87 mol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 30a-2 (4.6 g), a yellow oil.

[0167] Step 2: 1-(4-chlorothiazol-2-yl)-3-methoxypropyl-1-one 30a-3

[0168] 2-Bromo-4-chlorothiazol (6 g, 30.3 mol) was dissolved in THF (60 mL). Under ice bath conditions, isopropyl magnesium chloride-lithium chloride solution (1.3 M, 16.3 mL, 21.19 mol) was added dropwise, and the reaction was allowed to proceed for 0.5 h under ice bath conditions. Then, compound 30a-2 (4.6 g, 31.2 mol) was added dropwise, and the reaction was allowed to proceed for 2 h at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added dropwise to the reaction mixture at 0 °C. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 24 / 1) to obtain compound 30a-3 (2 g), a yellow oil.

[0169] MS(ESI) m / z 205.9 [M+H] +

[0170] Step 3: 4-Chloro-2-(1,1-difluoro-3-methoxypropyl)thiazole 30a-4

[0171] Compound 30a-3 (2 g, 9.7 mol) was dissolved in BAST (20 mL) and reacted overnight at room temperature. The reaction solution was diluted with DCM (200 mL) and the reaction was quenched by dropwise addition to a saturated sodium bicarbonate solution at 0 °C. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give compound 30a-4 (1.7 g), a yellow oil.

[0172] MS(ESI) m / z 228.0 [M+H] +

[0173] Step 4: Synthesis of compound 30a

[0174] Compound 30a-4 (1.7 g, 7.4 mol) was dissolved in THF (20 mL). A solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (22.4 mL, 1.0 M, 22.2 mol) was added dropwise at -78 °C under nitrogen protection. After 0.5 h of reaction, diethyl pyrocarbonate (3.6 g, 22.2 mol) was added dropwise to the reaction solution, and the reaction was continued at -78 °C for 2 h. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE) to obtain compound 30a (2 g), a yellow oil.

[0175] MS(ESI)m / z 300[M+H] +

[0176] Intermediate 32a: Ethyl 4-chloro-2-(2,2-difluorocyclopropyl)thiazole-5-carboxylate

[0177] Step 1: 1,3-Dioxoisoindoline-2-yl 2,2-difluorocyclopropyl-1-carboxylate 32a-2

[0178] Compound 32a-1 (5.0 g, 40.96 mmol) and DMAP (0.5 g, 4.10 mmol) were dissolved in DCM (100 mL). After cooling to 0 °C, DCC (10.14 g, 49.15 mmol) was added. After stirring for 30 minutes, N-hydroxyphthalimide (8.02 g, 49.15 mmol) was added, and the mixture was slowly heated to 25 °C and reacted for 12 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with DCM. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / DCM = 1 / 1) to give a pale yellow solid 32a-2 (7.0 g).

[0179] MS(ESI) m / z 268.0 [M+H] +

[0180] Step 2: 2-(2,2-difluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentane 32a-3

[0181] Compound 32a-2 (13.0 g, 48.65 mmol) and bis(pinacol)diboron (13.59 g, 53.52 mmol) were dissolved in ethyl acetate (130 mL), purged three times with argon, heated to 85 °C, and then tert-butyl isonicotinic acid (1.74 g, 9.73 mmol) was added. The reaction was carried out at 85 °C for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 98 / 2) to give a yellow oily substance 32a-3 (1.0 g).

[0182] Step 3: Synthesis of compound 32a

[0183] Compounds 32a-3 (1.41 g, 6.90 mmol) and 32a-4 (1.30 g, 5.75 mmol) were dissolved in 1,4-dioxane (10 mL), and Pd(dppf)Cl2 (420 mg, 0.58 mmol), H2O (1 mL), and K2CO3 (2.38 g, 17.25 mmol) were added. After purging with argon three times, the reaction was carried out at 85 °C for 18 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 98 / 2) to give a colorless oily substance 32a (300 mg).

[0184] MS(ESI) m / z 267.9 [M+H] +

[0185] Intermediate 34a: Ethyl 4-chloro-2-(1-cyclopropylethyl)thiazole-5-carboxylate

[0186] Step 1: Ethyl 4-chloro-2-(1-cyclopropylvinyl)thiazolyl-5-carboxylate 34a-2

[0187] Ethyl 2,4-dichlorothiazol-5-carboxylate (2.0 g, 8.85 mmol) and compound 34a-1 (2.58 g, 13.27 mmol) were dissolved in 1,4-dioxane (20 mL). Pd(dppf)Cl2 (647 mg, 0.88 mmol), H2O (5 mL), and K3PO4 (3.76 g, 17.69 mmol) were added. After purging with argon three times, the reaction was carried out at 90 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 34a-2 (1.50 g), a yellow oil.

[0188] MS(ESI) m / z 257.9 [M+H] +

[0189] Second step: Synthesis of compound 34a

[0190] Compound 34a-2 (0.5 g, 1.94 mmol) was dissolved in THF (10 mL), and Pd / C (100 mg, 10% Pd, 55% water) was added. The mixture was purged with hydrogen three times, and the reaction was carried out at room temperature for 18 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 34a (100 mg), a yellow oil.

[0191] MS(ESI) m / z 260.0 [M+H] +

[0192] Intermediate 44b: Ethyl 4-chloro-2-(2-cyanocyclopropyl)thiazole-5-carboxylate

[0193] The synthesis of compound 44a is based on J. Am. Chem. Soc. 2013, 135, 3375-3378. Compounds 32a-4 (50 mg, 0.22 mmol) and 44a (51 mg, 0.26 mmol) were dissolved in 1,4-dioxane (2 mL), and Pd(dppf)Cl2 (16 mg, 0.022 mmol), H2O (0.4 mL), and potassium carbonate (61 mg, 0.44 mmol) were added. After three purgings with argon, the reaction was carried out at 85 °C for 18 h. After the reaction was complete, the crude product was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 44b (40 mg).

[0194] MS(ESI) m / z 257.1 [M+H] +

[0195] 1 H NMR (400MHz, CDCl3) δ4.36 (q, J=7.1Hz, 2H), 2.83 (ddd, J=8.8, 6.1, 4.3Hz, 1H), 2.21 (ddd, J=9.1, 6. 3,4.3Hz,1H),1.86(dt,J=9.2,5.7Hz,1H),1.79(ddd,J=8.9,6.2,5.2Hz,1H),1.38(t,J=7.1Hz,3H).

[0196] Intermediate 45a: Ethyl 4-bromo-2-(3-fluorotetrahydrofuran-3-yl)thiazolyl-5-carboxylate

[0197] Step 1 3-(4-bromothiazo-2-yl)tetrahydrofuran-3-ol 45a-1

[0198] Compound 1a (20.0 g, 82.33 mmol) was dissolved in THF (200 mL), and a tetrahydrofuran solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (69.67 mL, 1.3 M, 90.57 mmol) was added dropwise at -10 °C under nitrogen protection for 0.5 h. Then, dihydro-3(2H)-furanone (8.51 g, 98.80 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture, and the reaction continued for 2.5 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture under low temperature conditions, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 85 / 15) to give compound 45a-1 (10.0 g), a yellow oil.

[0199] MS(ESI) m / z 250.0 [M+H] +

[0200] Step 2: 4-Bromo-2-(3-fluorotetrahydrofuran-3-yl)thiazole 45a-2

[0201] Compound 45a-1 (6.5 g, 25.99 mmol) was dissolved in DCM (70 mL), and DAST (4.61 g, 28.59 mmol) was added dropwise at -78 °C. The reaction was carried out under nitrogen protection for 1.5 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to the reaction mixture under low temperature conditions, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 45a-2 (4.0 g), a yellow oil.

[0202] MS(ESI) m / z 252.0 [M+H] +

[0203] Step 3: Ethyl 4-bromo-2-(3-fluorotetrahydrofuran-3-yl)thiazolyl-5-carboxylate 45a-3

[0204] Compound 45a-2 (4.0 g, 5.13 mmol) was dissolved in THF (50 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (31.73 mL, 1.0 M, 31.73 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. Then, diethyl pyrocarbonate (5.15 g, 31.73 mmol) was dissolved in THF and added dropwise to the reaction mixture. After the addition was complete, the mixture was heated to room temperature and reacted for 18 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice bath conditions, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain compound 45a-3 (3.5 g), a yellow oil.

[0205] MS(ESI) m / z 324.1 [M+H] +

[0206] Intermediate 46a((S,E)-3-amino-3-cyclopropyl-1-en-1-yl)methanesulfonylimide hydrochloride

[0207] Step 1 ((1S,E)-3-(N-(tert-Butoxycarbonyl)-Methylsulfonylimide)-1-Cyclopropylallyl)tert-butyl carbamate 46a-3

[0208] Compound 46a-1 (synthesized according to method WO2025073792, 130 mg, 0.4 mmol) was dissolved in THF (3 mL), and sodium hydride (18 mg, 60%, 0.44 mmol) was added at 0 °C. The reaction was continued at 0 °C for 1 h. Then, a THF solution of compound 46a-2 (80 mg, 0.4 mmol) in 2 mL was added dropwise, and the reaction was continued at 0 °C for another 1 h. The reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound 46a-3 (152 mg), a white solid.

[0209] MS(ESI) m / z 375.3 [M+H] +

[0210] Second step: Synthesis of compound 46a

[0211] Compound 46a-3 (135 mg, 0.36 mmol) was dissolved in ethyl acetate (2 mL), and HCl (2 mL, 4.0 M in ethyl acetate) was added. The reaction was carried out at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound 46a (115 mg), a white solid. The crude product was used directly in the next step.

[0212] MS(ESI) m / z 349.3 [2M+H] +

[0213] Intermediate 47a((R,E)-3-amino-3-cyclopropyl-1-en-1-yl)methanesulfonylimide hydrochloride

[0214] The synthesis of compound 47a is based on 46a, with compound 47a-1 replacing 46a-2. MS (ESI) m / z 349.3 [2M+H] +

[0215] Intermediate 49a ethyl 4-[(2-fluoropyridin-3-yl)oxy]-2-(3-methyltetrahydrofuran-3-yl)thiazolyl-5-carboxylate

[0216] Step 1: Ethyl 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)thiazolyl-5-carboxylate 49a-2

[0217] Compound 32a-4 (6.0 g, 26.52 mmol) was dissolved in 1,4-dioxane (60 mL) and water (12 mL). Compound 49a-1 (5.84 g, 27.8 mmol), potassium carbonate (9.14 g, 66.3 mmol), and Pd(dppf)Cl2 (193 mg, 0.265 mmol) were added. The reaction system was purged with nitrogen three times and reacted at 90 °C. After the reaction was complete, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 49a-2 (5.2 g).

[0218] MS(ESI) m / z 274.1 [M+H] +

[0219] Step 2: 2-(3,7-dioxabicyclo[4.1.0]heptane-6-yl)-4-chlorothiazol-5-carboxylic acid ethyl 49a-3

[0220] Compound 49a-2 (5.1 g, 18.6 mmol) was dissolved in dichloromethane (50 mL), and m-CPBA (15 g, 74.4 mmol, 85%) was added at 0 °C, followed by a return to room temperature. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 49a-3 (4 g).

[0221] MS(ESI) m / z 290.2 [M+H] +

[0222] Step 3: Ethyl 4-chloro-2-(3-formyltetrahydrofuran-3-yl)thiazolyl-5-carboxylate 49a-4

[0223] Compound 49a-3 (2 g, 6.89 mmol) was dissolved in dichloromethane (20 mL), and boron trifluoride diethyl ether (4.89 g, 34 mmol) was added at 0 °C. The reaction was then brought back to room temperature. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 49a-4 (2 g).

[0224] MS(ESI) m / z 290.1 ​​[M+H] +

[0225] Step 4: 2-(3-(1,3-dithiacyclopentan-2-yl)tetrahydrofuran-3-yl)-4-chlorothiazol-5-carboxylic acid ethyl ester 49a-5

[0226] Compound 49a-4 (90 mg, 0.31 mmol) and ethylenedithiol (58 mg, 0.62 mmol) were dissolved in dichloromethane (5 mL), and BF3·OEt (0.038 mL, 0.31 mmol) was added dropwise at room temperature. The reaction was allowed to proceed for 2 h at room temperature. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The collected organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel plate to give compound 49a-5 (80 mg).

[0227] Step 5: Ethyl 4-chloro-2-(3-methyltetrahydrofuran-3-yl)thiazolyl-5-carboxylate 49a

[0228] Compound 49a-5 (950 mg, 2.60 mmol) was dissolved in ethanol (100 mL), and Raney nickel (4 g) was added. After reacting at room temperature for 24 hours, Raney nickel (4 g) was added again, and the reaction continued for another 24 hours. After the reaction was complete, Raney nickel was removed by diatomaceous earth filtration, and the mixture was washed with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 92 / 8) to obtain compound 49a (200 mg), a colorless oil.

[0229] MS(ESI) m / z 276.1 [M+H] +

[0230] Example 1: N-[(1S,2E)-1-cyclopropyl-3-(methyldioxane-λ)] 6 [-mercapto)-prop-2-enyl]-2-methyl-4-(phenoxy)-thiazolyl-5-carboxamide

[0231] Step 1 4-bromo-2-methylthiazole 1b

[0232] Compound 1a (10 g, 41.6 mmol) was dissolved in tetrahydrofuran (100 mL), and methylboronic acid (2.75 g, 45.8 mmol), potassium phosphate (26.5 g, 124.8 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (3.61 g, 6.24 mmol), and palladium acetate (0.93 g, 4.16 mmol) were added. The reaction system was purged with nitrogen three times. The reaction was carried out overnight at 60 °C under nitrogen protection. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 1b (8 g).

[0233] MS(ESI) m / z 179.8 [M+H] +

[0234] Step 2: Ethyl 4-bromo-2-methylthiazole-5-carboxylate 1c

[0235] Compound 1b (4 g, 22.5 mmol) was dissolved in tetrahydrofuran (40 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (24.8 mL, 1.0 M, 24.7 mmol) was added dropwise at -78 °C. The reaction was carried out under nitrogen protection for 0.5 h. Then, diethyl pyrocarbonate (3.67 g, 22.5 mmol) was added dropwise to the reaction mixture, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution at 0 °C, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1c (2.5 g).

[0236] MS(ESI) m / z 250.1 [M+H] +

[0237] Step 3: Ethyl 2-methyl-4-(phenoxy)-thiazolyl-5-carboxylate (1 day)

[0238] Compound 1c (1.2 g, 4.85 mmol) was dissolved in N-methylpyrrolidone (10 mL), and potassium phenolate (0.96 g, 7.28 mmol) was added. The mixture was reacted at 90 °C for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 1d (100 mg).

[0239] MS(ESI) m / z 264.0 [M+H] +

[0240] Step 4: 2-Methyl-4-(phenoxy)-thiazolyl-5-carboxylic acid 1e

[0241] Compound 1d (100 mg, 0.38 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (45 mg, 1.9 mmol) was added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, the pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the crude product, compound 1e (50 mg).

[0242] MS(ESI) m / z 236.0 [M+H] +

[0243] Step 5: N-[(1S,2E)-1-cyclopropyl-3-(methyldioxane-λ)] 6 [-mercapto)-prop-2-enyl]-2-methyl-4-(phenoxy)-thiazolyl-5-carboxamide

[0244] The synthesis of (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate was performed according to WO2024010782. Compound 1e (50 mg, 0.21 mmol) was dissolved in DMF (1 mL), and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (73.5 mg, 0.21 mmol), DIEA (135 mg, 1.06 mmol), and HATU (241 mg, 0.63 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the product was concentrated under reduced pressure to obtain the crude product. Compound 1 (47.2 mg) was purified by preparative HPLC as a white solid.

[0245] MS(ESI) m / z 393.1 [M+H] +

[0246] 1 H NMR (400MHz, CDCl3) δ7.47-7.40(m,2H),7.28(s,1H),7.25-7.15(m,3H),6.98(dd,J=15.1,4.6Hz,1H),6.50(dd,J=15.2,2.0Hz ,1H),4.19-4.12(m,1H),2.93(s,3H),2.63(s,3H),1.06-0.95(m,1H),0.73-0.65(m,1H),0.63-0.56(m,1H),0.49-0.38(m,2H).

[0247] Example 2 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-phenylthiazol-5-carboxamide

[0248] Step 1 4-Bromo-2-phenyl-1,3-thiazole 2a

[0249] Compound 1a (10 g, 41.6 mmol) was dissolved in tetrahydrofuran (100 mL), and phenylboronic acid (5.08 g, 41.6 mmol), potassium phosphate (26.5 g, 124.8 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (3.61 g, 6.24 mmol), and palladium acetate (0.93 g, 4.16 mmol) were added. The reaction system was purged with nitrogen three times. The reaction was carried out overnight at 60 °C under nitrogen protection. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 99 / 1) to give compound 2a (7.8 g).

[0250] MS(ESI) m / z 239.9 [M+H] +

[0251] Step 2: Ethyl 4-bromo-2-phenyl-1,3-thiazo-5-carboxylic acid 2b

[0252] Compound 2a (3 g, 12.6 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (13.8 mL, 1.0 M, 13.8 mmol) was added dropwise at -78 °C. The reaction was carried out under nitrogen protection for 0.5 h. Diethyl pyrocarbonate (2.0 g, 12.6 mmol) was then added dropwise to the reaction solution, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2b (2.0 g).

[0253] MS(ESI) m / z 311.9 [M+H] +

[0254] Step 3: Ethyl 2-phenyl-4-benzyloxy-1,3-thiazolyl-5-carboxylate 2c

[0255] Compound 2b (1.0 g, 3.22 mmol) was dissolved in N-methylpyrrolidone (10 mL), and potassium phenolate (0.85 g, 6.44 mmol) was added. The mixture was reacted at 90 °C for 2 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2c (200 mg), a yellow oil.

[0256] MS(ESI) m / z 326.1 [M+H] +

[0257] Step 4: 2-Phenylacetyl-4-benzyloxy-1,3-thiazolyl-5-carboxylic acid 2d

[0258] Compound 2c (100 mg, 0.31 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (36.8 mg, 1.9 mmol) was added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, the pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give crude product 2d (80 mg).

[0259] MS(ESI) m / z 298.0 [M+H] +

[0260] Step 5 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-phenylthiazol-5-carboxamide 2

[0261] Compound 2d (80 mg, 0.27 mmol) was dissolved in DMF (1 mL), and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (93.4 mg, 0.27 mmol), DIEA (172.3 mg, 1.35 mmol), and HATU (307.1 mg, 0.81 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the crude product was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 2 (38.8 mg).

[0262] MS(ESI) m / z 455.1 [M+H] +

[0263] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=6.8Hz,2H),7.50-7.37(m,5H),7.32-7.22(m,3H),7.00(dd,J=15.2,4.6Hz,1H),6.53(dd,J=1 5.1,2.0Hz,1H),4.23-4.12(m,1H),2.93(s,3H),1.06-0.97(m,1H),0.74-0.66(m,1H),0.65-0.57(m,1H),0.51-0.40(m,2H).

[0264] Example 3 (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0265] Step 1 4-Bromo-2-cyclopropyl-1,3-thiazole 3a

[0266] Compound 1a (5 g, 20.8 mmol) was dissolved in tetrahydrofuran (50 mL), and cyclopropylboronic acid (2.0 g, 22.8 mmol), potassium phosphate (13.25 g, 62.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.83 g, 3.12 mmol), and palladium acetate (0.47 g, 2.08 mmol) were added. The reaction system was purged with nitrogen three times. The reaction was carried out overnight at 60 °C under nitrogen protection. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 19 / 1) to give a white solid 3a (2.5 g).

[0267] MS(ESI) m / z 203.8 [M+H] +

[0268] Step 2: Ethyl 4-bromo-2-cyclopropyl-1,3-thiazo-5-carboxylate 3b

[0269] Compound 3a (2.0 g, 10.1 mmol) was dissolved in tetrahydrofuran (20 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (10 mL, 1.0 M, 11.11 mmol) was added dropwise at -78 °C. The reaction was carried out under nitrogen protection for 0.5 h, followed by the addition of diethyl pyrocarbonate (1.6 g, 10.1 mmol). The reaction was then allowed to return to room temperature for 2 h. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction mixture at 0 °C, followed by extraction with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a white solid 3b (1.5 g).

[0270] MS(ESI) m / z 276.0 [M+H] +

[0271] Step 3: Ethyl 2-cyclopropyl-4-benzyloxy-1,3-thiazolyl-5-carboxylate 3c

[0272] Compound 3b (1.0 g, 3.63 mmol) was dissolved in N-methylpyrrolidone (10 mL), and potassium phenolate (0.72 g, 5.45 mmol) was added. The mixture was reacted at 90 °C for 2 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 97 / 3) to give a yellow oily substance 3c (100 mg).

[0273] MS(ESI) m / z 290.0 [M+H] +

[0274] Step 4: 2-Cyclopropyl-4-benzyloxy-1,3-thiazolyl-5-carboxylic acid 3d

[0275] Compound 3c (100 mg, 0.34 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (41 mg, 1.72 mmol) was added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution, the pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the crude product, a yellow oily substance 3d (60 mg).

[0276] MS(ESI) m / z 262.0 [M+H] +

[0277] Step 5: (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0278] Compound 3d (60 mg, 0.23 mmol) was dissolved in DMF (1 mL), and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (80 mg, 0.23 mmol), DIEA (147.2 mg, 1.15 mmol), and HATU (262.2 mg, 0.69 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 3 (2 mg), a white solid.

[0279] MS(ESI) m / z 419.1 [M+H] +

[0280] 1 H NMR (400MHz, CDCl3) δ7.44-7.37(m,2H),7.22(t,J=7.4Hz,1H),7.17-7.14(m ,3H),6.97(dd,J=15.1,4.6Hz,1H),6.47(dd,J=15.1,1.9Hz,1H),4.19-4.05( m,1H),2.90(s,3H),2.25-2.14(m,1H),1.20-1.11(m,2H),1.04-0.98(m,2H) ,0.99-0.92(m,1H),0.70-0.62(m,1H),0.61-0.52(m,1H),0.46-0.35(m,2H).

[0281] Example 4 (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-Ethyl-4-phenoxythiazol-5-carboxamide

[0282] Step 1 4-bromo-2-vinylthiazole 4a

[0283] Compound 1a (5 g, 20.5 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane (3.81 g, 24.6 mmol), Pd(dppf)Cl2 (1.49 g, 2.05 mmol), and K2CO3 (8.48 g, 61.5 mmol) were dissolved in Dioxane (80 mL) and H2O (20 mL), purged three times with nitrogen, and reacted at 80 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 5:1) to give compound 4a (2.8 g), a white solid.

[0284] MS(ESI) m / z 189.9 [M+H] +

[0285] Step 2: Ethyl 4-bromo-2-ethylthiazole-5-carboxylate 4b

[0286] Compound 4a (2.8 g, 14.7 mmol) and Pd / C (2 g, 10%) were dissolved in MeOH (50 mL) and reacted at 50 °C for 16 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, concentrated, and the crude product was purified by column chromatography to obtain compound 4b (1.5 g), a white solid.

[0287] MS(ESI) m / z 191.9 [M+H] +

[0288] Step 3: Ethyl 4-bromo-2-ethylthiazole-5-carboxylate 4c

[0289] Compound 4b (900 mg, 4.73 mmol) was dissolved in THF (10 mL), and TMPLi (5.68 mL, 1 M, 5.68 mmol) was added at -78 °C. After reacting for 30 min at -78 °C, ethyl oxane formic anhydride (920 mg, 5.68 mmol) was added, and the reaction was carried out at -78 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 4:1) to obtain compound 4c (800 mg), a pale yellow solid.

[0290] MS(ESI) m / z 264.0 [M+H] +

[0291] Step 4: 2-Ethyl-4-phenoxythiazole-5-carboxylic acid 4d

[0292] Compound 4c (300 mg, 1.13 mmol), phenol (128 mg, 1.36 mmol), CuI (21.4 mg, 113 μmol), 1,10-phenanthroline (40.6 mg, 226 μmol), and Cs₂CO₃ (916 mg, 2.82 mmol) were dissolved in DMF (10 mL), purged three times with nitrogen, and reacted at 80 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 4:1) to give compound 4d (60 mg), a white solid.

[0293] MS(ESI) m / z 278.1 [M+H] +

[0294] Step 5: 2-Ethyl-4-phenoxythiazole-5-carboxylic acid 4e

[0295] Compound 4d (60 mg, 0.21 mmol) was dissolved in THF (2 mL) and water (0.5 mL), and LiOH (20.1 mg, 0.84 mmol) was added. The reaction was carried out at 25 °C for 16 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1.0 M dilute hydrochloric acid, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 4e (40 mg), a pale yellow liquid.

[0296] MS(ESI) m / z 250.0 [M+H] +

[0297] Step 6 (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-Ethyl-4-phenoxythiazol-5-carboxamide 4

[0298] Compound 4e (40 mg, 160 μmol) and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (83.2 mg, 240 μmol) were dissolved in DMF (1 mL), and HATU (91.2 mg, 240 μmol) and DIEA (61.9 mg, 480 μmol) were added. The mixture was reacted at 25 °C for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain compound 4 (44 mg) as a white solid.

[0299] MS(ESI) m / z 407.1 [M+H] +

[0300] 1H NMR (400MHz, CDCl3) δ7.44–7.40(m,2H),7.24–7.14(m,4H),6.97(dd,J=15.2,4.6Hz,1H),6.49(dd,J=15.1,1.7Hz,1H),4.21–4.08(m,1H) ,2.98–2.85(m,5H),1.33(t,J=7.5Hz,3H),1.04–0.94(m,1H),0.67(td,J=8.3,4.1Hz,1H),0.58(td,J=8.9,4.7Hz,1H),0.49–0.36(m,2H).

[0301] Example 5 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxamide

[0302] Step 1 4-bromo-2-(prop-1-en-2-yl)thiazole 5a

[0303] Compound 1a (5 g, 20.5 mmol), potassium isopropenyltrifluoroborate (3.4 g, 20.5 mmol), Pd(dppf)Cl2 (0.74 g, 1.02 mmol), and K2CO3 (7.1 g, 51.3 mmol) were dissolved in 1,4-dioxane (50 mL) and H2O (10 mL). The mixture was purged with nitrogen three times and reacted at 80 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to give compound 5a (3.1 g), a yellow oily liquid.

[0304] MS(ESI) m / z 203.9 [M+H] +

[0305] Step 2: 1-(4-bromothiazo-2-yl)ethane-1-one 5b

[0306] Compound 5a (2.0 g, 9.8 mmol) was dissolved in THF (200 mL) and H₂O (100 mL). K₂O₅₂O₄·2H₂O (360 mg, 0.98 mmol) and NaIO₄ (10.4 g, 49 mmol) were added sequentially to the reaction solution. After the reaction was complete, the solution was filtered and concentrated. The solution was diluted with water and extracted three times with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to give compound 5b (1.3 g), a white solid.

[0307] MS(ESI) m / z 205.9 [M+H] +

[0308] Step 3: 4-Bromo-2-(1,1-difluoroethyl)thiazole 5c

[0309] Compound 5b (1.25 g, 6.1 mmol) was dissolved in DCM (25 mL), and BAST (13 mL) was added at 25 °C. The reaction was carried out at 25 °C for 16 h. After the reaction was completed, the reaction solution was slowly added dropwise to an ice-cold saturated aqueous solution of Na₂S₂O₃. The pH was adjusted to 8 with saturated NaHCO₃ aqueous solution. The mixture was extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 5c (850 mg), a yellow oily liquid.

[0310] 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 2.20-2.07 (m, 3H).

[0311] Step 4: Ethyl 4-bromo-2-(1,1-difluoroethyl)thiazole-5-carboxylate (5 days)

[0312] Compound 5c (550 mg, 2.16 mmol) was dissolved in THF (5 mL). A tetrahydrofuran solution (6.5 mL, 1 M, 6.5 mmol) of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex was added at -78 °C. After reacting for 30 min at -78 °C, ethyl oxane carboxylic anhydride (1.05 g, 6.5 mmol) was added, and the reaction was continued at -78 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 5d (400 mg), a yellow oily liquid.

[0313] 1 H NMR (400MHz, CDCl3) δ4.40 (q, J=14.4, 7.2Hz, 2H), 2.15-2.06 (m, 3H), 1.39 (t, J=7.2Hz, 3H).

[0314] Step 5: 2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 5e

[0315] Compound 5d (100 mg, 0.32 mmol), phenol (36 mg, 0.38 mmol), CuI (60.8 mg, 0.32 mmol), 1,10-Phenanthroline (57.6 mg, 0.32 mmol), and Cs₂CO₃ (324 mg, 0.96 mmol) were dissolved in DMF (2 mL), purged three times with nitrogen, and reacted at 100 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to give compound 5e (50 mg), a yellow oily liquid.

[0316] MS(ESI) m / z 314.0 [M+H] +

[0317] Step 6: 2-(1,1-Difluoroethyl)-4-phenoxythiazole-5-carboxylic acid 5f

[0318] Compound 5e (40 mg, 0.13 mmol) was dissolved in THF (1 mL) and H₂O (1 mL), and LiOH (29 mg, 1.3 mmol) was added. The reaction was carried out at 25 °C for 2 h. After the reaction was complete, the pH of the reaction solution was adjusted to 3 with 1.0 M dilute hydrochloric acid, extracted with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 5f (15 mg) as a yellow solid.

[0319] MS(ESI) m / z 286.0 [M+H] +

[0320] Step 7 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxamide 5

[0321] Compound 5f (15 mg, 53 μmol) and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (14 mg, 79 μmol) were dissolved in DMF (1 mL), and HATU (30 mg, 79 μmol) and DIEA (20 mg, 158 μmol) were added. The mixture was reacted at 25 °C for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high performance liquid chromatography to obtain compound 5 (3.6 mg) as a white solid.

[0322] MS(ESI) m / z 443.0 [M+H] +

[0323] 1 H NMR (400MHz, CDCl3) δ7.45 -7.41(m,2H),7.29-7.27(m,1H),7.19-7.16(m,2H),7.00-6.95(m,1H),6.53-6.49(m,1H),4.18-4.12(m,1H),2.93(s, 3H),2.04-1.92(m,3H),1.03-1.00(m,1H),0.86-0.82(m,1H),0.73-0.69(m,1H),0.63-0.61(m,1H),0.46-0.42(m,2H).

[0324] Example 6 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxamide

[0325] Step 1 4-bromo-2-(1-cyclopropylvinyl)thiazole 6a

[0326] Compound 1a (11 g, 47 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (10 g, 52 mmol), Pd(dppf)Cl2 (3.36 g, 4.7 mmol), and K2CO3 (16 g, 118 mmol) were dissolved in Dioxane (100 mL) and H2O (10 mL), and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 20:1) to give compound 6a (8 g), a yellow oily liquid.

[0327] MS(ESI) m / z 229.9 [M+H] +

[0328] Step 2 (4-bromothiazo-2-yl)(cyclopropyl)methane 6b

[0329] Compound 6a (3.0 g, 13.1 mmol) was dissolved in THF (300 mL) and H₂O (150 mL). K₂O₂O₄·2H₂O (482 mg, 1.31 mmol) and NaIO₄ (14 g, 65.5 mmol) were added sequentially to the reaction solution. After the reaction was complete, the solution was filtered and concentrated. The solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to give compound 6b (1.0 g), a yellow solid.

[0330] MS(ESI) m / z 231.9 [M+H] +

[0331] Step 3: 4-Bromo-2-(cyclopropyldifluoromethyl)thiazole 6c

[0332] Compound 6b (1 g, 4.3 mmol) was dissolved in DAST (10 mL) and reacted at 80 °C for 16 h. After the reaction was complete, the reaction solution was slowly added dropwise to ice-cold saturated Na₂S₂O₃ aqueous solution. The pH was adjusted to 8 with saturated NaHCO₃ aqueous solution. The mixture was extracted three times with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound 6c (200 mg), a yellow oily liquid.

[0333] 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),3.22-3.16(m,1H),1.35-1.31(m,2H),1.21-1.16(m,2H).

[0334] Step 4: 2-(cyclopropyl difluoromethyl)-4-phenoxythiazole 6d

[0335] Compound 6c (100 mg, 0.39 mmol), phenol (39 mg, 0.42 mmol), CuI (74.1 mg, 0.39 mmol), 1,10-Phenanthroline (14 mg, 0.039 mmol), and Cs₂CO₃ (380 mg, 0.78 mmol) were dissolved in DMF (2 mL), purged three times with nitrogen, and reacted at 110 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound 6d (30 mg), a yellow oily liquid.

[0336] MS(ESI) m / z 268.1 [M+H] +

[0337] Step 5: 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 6e

[0338] Compound 6e (30 mg, 0.11 mmol) was dissolved in THF (1 mL). A tetrahydrofuran solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (0.33 mL, 1 M, 0.33 mmol) was added at -78 °C. After reacting for 30 min at -78 °C, ethyl oxane carboxylic anhydride (53 mg, 0.33 mmol) was added, and the reaction was continued at -78 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound 6e (30 mg), a yellow oily liquid.

[0339] MS(ESI) m / z 340.1 [M+H] +

[0340] Step 6: 2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxylic acid 6f

[0341] Compound 6e (30 mg, 0.09 mmol) was dissolved in THF (1 mL) and H₂O (1 mL), and LiOH (22 mg, 0.9 mmol) was added. The reaction was carried out at 25 °C for 2 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1.0 M dilute HCl, and the mixture was extracted three times with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 6f (20 mg) as a yellow solid.

[0342] MS(ESI) m / z 312.0 [M+H] +

[0343] Step 7 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxythiazole-5-carboxamide 6

[0344] Compound 6f (20 mg, 64 μmol) and (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine p-toluenesulfonate (17 mg, 96 μmol) were dissolved in DMF (1 mL), and HATU (36 mg, 96 μmol) and DIEA (25 mg, 192 μmol) were added. The mixture was reacted at 25 °C for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by high performance liquid chromatography to obtain compound 6 (5 mg) as a white solid.

[0345] MS(ESI) m / z 469.1 [M+H]+

[0346] 1 H NMR (400MHz, CDCl3) δ7.45-7.41(m,2H),7.28-7.27(m,1H),7.21-7.18(m,2H), 7.00-6.95(dd,J=15.2,4.8Hz,1H),6.53-6.49(dd,J=15.2,1.6Hz,1H),4.84-4 .31(m,1H),2.92(s,3H),1.46-1.37(m,1H),1.06–0.96(m,1H),0.88-0.86(m,1 H),0.81-0.79(m,2H),0.70-0.67(m,2H),0.65-0.59(m,1H),0.48-0.41(m,2H).

[0347] Example 7 (S,E)-2-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0348] Step 1 Cyclopentylthioformamide 7b

[0349] Compound 7a (1.0 g, 8.84 mmol) was dissolved in THF (20 mL), and Lawson's reagent (1.79 g, 4.42 mmol) was added. The reaction mixture was reacted at room temperature for 18 h. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, a yellow oily substance 7b (1.2 g). The crude product was used directly in the next step.

[0350] Step 2: 2-Cyclobutylpentylthiazole-5-carboxylic acid ethyl ester 7c

[0351] Compound 7b (1.0 g, 7.74 mmol, crude) was dissolved in acetic acid (5 mL), and ethyl (chloroformyl)acetate (2.33 g, 15.48 mmol) and p-toluenesulfonic acid (266 mg, 1.55 mmol) were added. The reaction mixture was purged with nitrogen three times and reacted overnight at 110 °C. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give a yellow oil 7c (1.1 g).

[0352] MS(ESI) m / z 226.0 [M+H] +

[0353] Step 3: Ethyl 2-cyclopentyl-4-iodothiazole-5-carboxylate (7 days)

[0354] Compound 7c (500 mg, 2.22 mmol) was dissolved in THF (5 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (2.45 mL, 1.0 M, 2.45 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. I₂ (1.24 g, 4.88 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was carried out at room temperature for 18 h. After the reaction was complete, the reaction was quenched by adding a saturated ammonium chloride solution at low temperature, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to obtain compound 7d (300 mg), a yellow oil.

[0355] MS(ESI) m / z 352.0 [M+H] +

[0356] Step 4: 2-Cyclopentyl-4-phenoxythiazole-5-carboxylic acid ethyl ester 7e

[0357] Compound 7d (300 mg, 0.85 mmol) was dissolved in DMF (3 mL), and phenol (241 mg, 2.56 mmol), 1,10-phenanthroline (31 mg, 0.17 mmol), cuprous iodide (16 mg, 0.09 mmol), and cesium carbonate (834 mg, 2.56 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 80 °C for 1 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to obtain compound 7e (30 mg), a yellow oil.

[0358] MS(ESI) m / z 318.1 [M+H] +

[0359] Step 5: 2-Cyclopentyl-4-phenoxythiazole-5-carboxylate 7f

[0360] Compound 7e (30 mg, 0.09 mmol) was dissolved in methanol (0.5 mL) and water (0.25 mL), and lithium hydroxide (11.3 mg, 0.47 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 7f (27 mg), a yellow oil. The crude product was used directly for the next step.

[0361] MS(ESI) m / z 290.1 ​​[M+H] +

[0362] Step 6 (S,E)-2-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide 7

[0363] Compound 7f (27 mg, 0.09 mmol) was dissolved in DMF (1 mL), and (S,E)-1-cyclopropyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (7 g) (46 mg, 0.14 mmol), DIEA (36 mg, 0.28 mmol), and HATU (71 mg, 0.19 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative HPLC to obtain compound 7 (7.2 mg) as a pale yellow solid.

[0364] MS(ESI) m / z 447.1 [M+H] +

[0365] 1 H NMR (400MHz, CDCl3) δ7.44-7.38(m,2H),7.25-7.13(m,4H),6.97(dd,J=15.2,4.6Hz,1H),6.47(dd,J=15.2,1.6Hz,1H),4.20-4.10(m,1H),3.3 7-3.25(m,1H),2.90(s,3H),2.17-2.07(m,2H),1.82-1.63(m,6H),1.03 -0.93(m,1H),0.71-0.62(m,1H),0.61-0.54(m,1H),0.46-0.36(m,2H).

[0366] Example 8 (S,E)-2-(1-cyanocyclopropyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0367] Step 1: 2-(2-(tert-butoxy)-1-cyano-2-oxaethyl)thiazole-5-carboxylic acid ethyl ester 8b

[0368] Compound 8a (10.0 g, 52.18 mmol) was dissolved in DMF (100 mL), and cesium carbonate (34.0 g, 104.37 mmol) and tert-butyl cyanoacetate (11.05 g, 78.28 mmol) were added. The mixture was reacted at 80 °C for 3 h. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to the crude product. The crude product was then purified by pulping (PE / EA = 5 / 1) to give compound 8b (14.0 g), a yellow solid.

[0369] MS(ESI) m / z 297.1 [M+H] +

[0370] Step 2: Ethyl 2-(cyanomethyl)thiazole-5-carboxylate 8c

[0371] Compound 8b (14.0 g, 47.24 mmol) was dissolved in 4 M hydrochloric acid (50 mL), and acetic acid (50 mL) was slowly added dropwise. The reaction was carried out at 70 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to give compound 8c (8.0 g), a yellow solid.

[0372] MS(ESI) m / z 196.9 [M+H] +

[0373] Step 3: Ethyl 2-(1-cyanocyclopropyl)thiazole-5-carboxylate (8 days)

[0374] Compound 8c (1.0 g, 5.10 mmol) was dissolved in DMF (10 mL). NaH (510 mg, 12.74 mmol, 60% purity) was added at room temperature, and the mixture was stirred for 10 minutes. Then, dibromoethane (1.91 g, 10.19 mmol) was added, and the mixture was reacted at room temperature for 18 h. After the reaction was complete, the reaction solution was quenched in saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 8d (500 mg), a yellow oil.

[0375] MS(ESI) m / z 222.9 [M+H] +

[0376] Step 4: 2-(1-Cyanocyclopropyl)-4-iodothiazole-5-carboxylic acid ethyl ester 8e

[0377] Compound 8d (0.5 g, 2.25 mmol) was dissolved in THF (10 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (6.75 mL, 1.0 M, 6.75 mmol) was added dropwise at -78°C, and the reaction was carried out under nitrogen protection for 1 h. I2 (1.71 g, 6.75 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was carried out at room temperature for 3 h. After the reaction was complete, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride at low temperature, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give a pink solid 8e (500 mg).

[0378] MS(ESI) m / z 348.8 [M+H] +

[0379] Step 5: 2-(1-Cyanocyclopropyl)-4-phenoxythiazole-5-carboxylic acid 8f

[0380] Compound 8e (200 mg, 0.57 mmol) was dissolved in DMF (3 mL), and potassium phenolate (380 mg, 2.87 mmol), 1,10-phenanthroline (21 mg, 0.11 mmol), and cuprous iodide (22 mg, 0.11 mmol) were added. The reaction system was purged with nitrogen three times. Under nitrogen protection, the reaction was carried out at 90 °C for 1 h. The reaction solution was cooled to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to give compound 8f (120 mg), a brown liquid. The crude product was used directly in the next step.

[0381] MS(ESI) m / z 287.0 [M+H] +

[0382] Step 6 (S,E)-2-(1-cyanocyclopropyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide 8

[0383] Compound 8f (120 mg crude) was dissolved in DMF (2 mL), and compound 7g (166 mg, 0.50 mmol), DIEA (162 mg, 1.26 mmol), and HATU (191 mg, 0.50 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound 8 (31.7 mg) as a white solid.

[0384] MS(ESI) m / z 444.0 [M+H] +

[0385] 1 H NMR (400MHz, CDCl3) δ7.43-7.38(m,2H),7.24(d,J=7.6Hz,1H),7.12-7.10(m,3H),6.97(dd,J=15.2,4.7Hz,1H),6.49(dd,J=15.2,1.7Hz,1H),4. 18-4.10(m,1H),2.93(s,3H),1.87-1.81(m,2H),1.79-1.70(m,2H),1.0 4-0.95(m,1H),0.71-0.66(m,1H),0.62-0.56(m,1H),0.47-0.38(m,2H).

[0386] Example 9 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(2-fluorophenoxy)thiazole-5-carboxamide

[0387] Step 1 4-Chloro-2-(1-ethoxyvinyl)thiazole 9b

[0388] Compound 9a (10 g, 65 mmol), tributyl(1-ethoxyethylene)tin (28 g, 78 mmol), and Pd(dppf)Cl2 (4.4 g, 0.65 mmol) were dissolved in 1,4-dioxane (100 mL), purged three times with nitrogen, and reacted at 100 °C for 16 h. After the reaction was complete, a saturated aqueous solution of potassium fluoride was added to the reaction solution and stirred at room temperature for 1 h. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography to obtain compound 9b (12 g), a yellow oily liquid.

[0389] Step 2: 1-(4-chlorothiazol-2-yl)ethyl-1-one 9c

[0390] Compound 9b (12 g, 63.4 mmol) was dissolved in 1,4-dioxane (120 mL), and 6M hydrochloric acid (60 mL) was added to the reaction solution. The reaction was carried out at room temperature for 4 h. After the reaction was complete, the reaction solution was concentrated. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography to obtain compound 9c (9.2 g), a yellow oily liquid.

[0391] 1 H NMR (400MHz, CDCl3) δ7.45 (s, 1H), 2.71 (s, 3H).

[0392] Step 3: 4-Chloro-2-(1,1-difluoroethyl)thiazole 9 days

[0393] Compound 9c (9.2 g, 57.1 mmol) was dissolved in BAST (50 mL) and reacted at room temperature for 16 h. After the reaction was complete, the reaction solution was slowly added dropwise to an ice-cold saturated aqueous solution of Na2S2O3 to adjust the pH to 8. The mixture was extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography to obtain compound 9d (11 g), a yellow oily liquid.

[0394] 1 H NMR (400MHz, CDCl3) δ7.19 (s, 1H), 2.10-2.00 (m, 3H).

[0395] Step 4: ethyl 4-chloro-2-(1,1-difluoroethyl)thiazole-5-carboxylate 9e

[0396] Compound 9d (11 g, 60 mmol) was dissolved in THF (110 mL), and a tetrahydrofuran solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (1680 mL, 1 M, 180 mmol) was added at -78 °C. After reacting for 4 h at -78 °C, diethyl pyrocarbonate (29.2 g, 180 mmol) was added, and the reaction was carried out at -78 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography to obtain compound 9e (13 g), a yellow oily liquid.

[0397] MS(ESI) m / z 255.9 [M+H] +

[0398] Step 5: 2-(1,1-difluoroethyl)-4-(2-fluorophenoxy)thiazole-5-carboxylic acid ethyl ester 9f

[0399] Compound 9e (200 mg, 0.78 mmol), o-fluorophenol (134 mg, 1.2 mmol), and potassium carbonate (320 mg, 2.34 mmol) were dissolved in DMF (2 mL) and reacted at 70 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 9f (150 mg), a yellow oily liquid.

[0400] MS(ESI) m / z 332.1 [M+H] +

[0401] Step 6: 9g of 2-(1,1-difluoroethyl)-4-(2-fluorophenoxy)thiazole-5-carboxylic acid

[0402] Compound 9f (150 mg, 0.45 mmol) was dissolved in THF (1 mL) and H2O (1 mL), and LiOH (31 mg, 1.36 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1 M hydrochloric acid, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 9 g (120 mg) as a yellow solid.

[0403] MS(ESI)m / z 304.0[M+H]+

[0404] Step 7 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(2-fluorophenoxy)thiazole-5-carboxamide 9

[0405] Compound 9 g (30 mg, 0.1 mmol) and compound 7 g (41.6 mg, 0.12 mmol) were dissolved in DMF (1 mL), and HATU (57 mg, 0.15 mmol) and DIEA (38 mg, 0.3 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to give compound 9 (16 mg) as a white solid.

[0406] MS(ESI) m / z 461.0 [M+H] +

[0407] 1 H NMR (400MHz, CDCl3) δ7.53-7.46(m,1H),7.35(d,J=7.4Hz,1H),7.25-7.18(m,3H),7.04-6.99(dd,J=15.2,4.7Hz,1H),6.60-6.56(dd, J=15.2,1.6Hz,1H),4.21-4.15(m,1H),2.96(s,3H),1.96(t,J=18.3Hz,3H),1.13-1.00(m,1H),0.77-0.62(m,2H),0.54-0.39(m,2H).

[0408] Example 10 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(3-fluorophenoxy)thiazole-5-carboxamide

[0409] Step 1: 2-(1,1-difluoroethyl)-4-(3-fluorophenoxy)thiazole-5-carboxylic acid ethyl ester 10a

[0410] Compound 9e (200 mg, 0.78 mmol), m-fluorophenol (134 mg, 1.2 mmol), and cesium carbonate (390 mg, 1.2 mmol) were dissolved in DMF (2 mL) and reacted at 80 °C for 4 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 10a (100 mg), a yellow oily liquid. The crude product was used directly in the next step.

[0411] MS(ESI) m / z 332.0 [M+H] +

[0412] Step 2: 2-(1,1-difluoroethyl)-4-(3-fluorophenoxy)thiazole-5-carboxylic acid 10b

[0413] Compound 10a (100 mg, 0.3 mmol) was dissolved in methanol (1 mL) and water (1 mL), and LiOH (69 mg, 3.0 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1 M hydrochloric acid, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10b (70 mg), a yellow solid.

[0414] MS(ESI) m / z 303.9 [M+H] +

[0415] Step 2: (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-(1,1-Difluoroethyl)-4-(3-Fluorophyl)thiazole-5-carboxamide 10

[0416] Compound 10b (70 mg, 0.23 mmol) and compound 7 g (96 mg, 0.28 mmol) were dissolved in DMF (1 mL), and HATU (133 mg, 0.35 mmol) and DIEA (94 mg, 0.69 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to give compound 10 (11 mg) as a white solid.

[0417] MS(ESI) m / z 461.0 [M+H] +

[0418] 1 H NMR (400MHz, CDCl3) δ7.43 -7.37(m,1H),7.15(d,J=7.4Hz,1H),7.02-6.93(m,4H),6.53(dd,J=15.2,1.6Hz,1H),4.17-4.11(m ,1H),2.94(s,3H),1.99(t,J=18.3Hz,3H),1.07-0.99(m,1H),0.75-0.60(m,2H),0.49-0.41(m,2H).

[0419] Example 11 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(4-fluorophenoxy)thiazole-5-carboxamide

[0420] Step 1: 2-(1,1-Difluoroethyl)-4-(4-fluorophenoxy)thiazole-5-carboxylic acid ethyl ester 11a

[0421] Compound 9e (200 mg, 0.78 mmol), p-fluorophenol (134 mg, 1.2 mmol), and cesium carbonate (390 mg, 1.2 mmol) were dissolved in DMF (2 mL) and reacted at 80 °C for 4 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 11a (150 mg), a yellow oily liquid. The crude product was used directly in the next step.

[0422] MS(ESI) m / z 332.0 [M+H] +

[0423] Step 2: 2-(1,1-difluoroethyl)-4-(4-fluorophenoxy)thiazole-5-carboxylic acid 11b

[0424] Compound 11b (150 mg, 0.45 mmol) was dissolved in methanol (1 mL) and water (1 mL), and LiOH (52 mg, 2.23 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1 M hydrochloric acid, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11b (90 mg) as a yellow solid.

[0425] MS(ESI) m / z 303.9 [M+H] +

[0426] Step 3 (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-(1,1-Difluoroethyl)-4-(4-Fluorophyl)thiazole-5-carboxamide 11

[0427] Compound 11b (90 mg, 0.3 mmol) and compound 7 g (124 mg, 0.36 mmol) were dissolved in DMF (1 mL), and HATU (171 mg, 0.45 mmol) and DIEA (123 mg, 0.9 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give compound 11 (50 mg) as a white solid.

[0428] MS(ESI) m / z 461.0 [M+H] +

[0429] 1H NMR (400MHz, CDCl3) δ7.23 -7.10(m,5H),6.98(dd,J=15.1,4.8Hz,1H),6.55(dd,J=15.2,1.5Hz,1H),4.19-4.13(m,1H), 2.95(s,3H),1.95(t,J=18.3Hz,3H),1.07-1.01(m,1H),0.74-0.61(m,2H),0.49-0.42(m,2H).

[0430] Example 12 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxamide

[0431] Step 1: 2-(1,1-difluoroethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxylic acid ethyl ester 12a

[0432] Compound 9e (200 mg, 0.78 mmol), 2-fluoropyridine-3-phenol (134 mg, 1.2 mmol), and cesium carbonate (390 mg, 1.2 mmol) were dissolved in DMF (2 mL) and reacted at 80 °C for 4 h. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 12a (70 mg), a yellow oily liquid.

[0433] MS(ESI) m / z 333.0 [M+H] +

[0434] Step 2: 2-(1,1-difluoroethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxylic acid 12b

[0435] Compound 12a (70 mg, 0.21 mmol) was dissolved in methanol (1 mL) and water (1 mL), and LiOH (24 mg) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1 M hydrochloric acid, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 12b (50 mg), a white solid.

[0436] MS(ESI) m / z 305.0 [M+H] +

[0437] Step 3: (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-(1,1-Difluoroethyl)-4-((2-Fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide 12

[0438] Compound 12b (50 mg, 0.16 mmol) and compound 7 g (70 mg, 0.2 mmol) were dissolved in DMF (1 mL), and HATU (91 mg, 0.24 mmol) and DIEA (66 mg, 0.48 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to give compound 12 (38 mg) as a white solid.

[0439] MS(ESI) m / z 462.0 [M+H] +

[0440] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=4.8Hz,1H),8.02-7.94(m,1H),7.32(dd,J=7.9,4.9Hz,1H),7.23(d,J=8.0Hz,1H),7.00(dd,J=15.2,4.8Hz,1H) ,6.59(dd,J=15.2,1.6Hz,1H),4.19-4.13(m,1H),2.96(s,3H),1.96(t, J=20.0Hz,3H),1.12-1.03(m,1H),0.78-0.65(m,2H),0.53-0.42(m,2H).

[0441] Example 13N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-methylcyclopropyl)-4-phenoxythiazole-5-carboxamide

[0442] Step 1 2-Methylcyclopropane-1-methylamide 13b

[0443] Compound 13a (1.5 g, 15 mmol) was dissolved in THF (15 mL), and Lawson's reagent (6.3 g, 15 mmol) and sodium carbonate (2.1 g, 15 mmol) were added. The mixture was reacted at 80 °C for 2 h. The reaction solution was cooled to room temperature, and water and ethyl acetate were added. The mixture was extracted three times, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 13b (1.3 g).

[0444] MS(ESI) m / z 115.9 [M+H] +

[0445] Step 2: Ethyl 2-(2-methylcyclopropyl)thiazole-5-carboxylate 13c

[0446] Compound 13b (1.2 g, 10.5 mmol) was dissolved in acetic acid (12 mL), and ethyl 2-chloro-2-formyl acetate (3.24 g, 21 mmol) and p-toluenesulfonic acid (360 mg, 2.1 mmol) were added. The mixture was reacted at 110 °C for 2 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 13c (230 mg).

[0447] MS(ESI) m / z 212.0 [M+H] +

[0448] Step 3: Ethyl 4-iodo-2-(2-methylcyclopropyl)thiazole-5-carboxylate 13d

[0449] Compound 13c (230 mg, 1.1 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (3.3 mL, 1.0 M, 3.3 mmol) was added dropwise at -78 °C under nitrogen protection for 1 h. Iodine (559 mg, 2.2 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was allowed to proceed at room temperature for 2 h, followed by extraction with saturated ammonium chloride solution and ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 13d (110 mg).

[0450] MS(ESI) m / z 337.9 [M+H] +

[0451] Step 4: 2-(2-methylcyclopropyl)-4-phenoxythiazole-5-carboxylic acid 13e

[0452] Compound 13d (110 mg, 0.33 mmol), potassium phenolate (215 mg, 1.63 mmol), 1,10-phenanthroline (12 mg, 0.07 mmol), and cuprous iodide (13 mg, 0.07 mmol) were dissolved in DMF (1 mL). The reaction system was purged with nitrogen three times and reacted at 90 °C for 1 h. The reaction solution was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The pH of the aqueous phase was adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate again. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 13e (60 mg).

[0453] MS(ESI) m / z 276.0 [M+H] +

[0454] Step 5: N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-methylcyclopropyl)-4-phenoxythiazole-5-carboxamide 13

[0455] Compound 13e (60 mg, 0.22 mmol) and compound 7 g (90 mg, 0.26 mmol) were dissolved in DMF (1 mL), and HATU (125 mg, 0.33 mmol) and DIEA (60 mg, 0.44 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give compound 13 (19 mg) as a white solid.

[0456] MS(ESI) m / z 433.1 [M+H] +

[0457] 1 H NMR (400MHz, CDCl3) δ7.40(t,J=7.6Hz,2H),7.22(t,J=7.6Hz,1H),7.15(d,J=8.0Hz,3H ),6.99-6.94(dd,J=15.2,4.8Hz,1H),6.48-6.44(dd,J=15.2,2.0Hz,1H),4.15-4.10(m ,1H),2.90(s,3H),1.93-1.88(m,1H),1.42-1.32(m,1H),1.21-1.18(m,1H),1.16(d,J= 6.0Hz,3H),1.01-0.92(m,2H),0.68-0.63(m,1H),0.59-0.54(m,1H),0.44-0.36(m,2H).

[0458] Example 14 (S,E)-2-tert-butyl-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0459] Step 1: 2-tert-butyl-thiazole-5-carboxylic acid ethyl ester 14b

[0460] Compound 14a (5 g, 42.7 mmol) was dissolved in acetic acid (50 mL), and ethyl (chloroformyl)acetate (6.7 g, 44.8 mmol) and p-toluenesulfonic acid (1.46 g, 8.54 mmol) were added. The reaction mixture was purged with nitrogen three times and reacted overnight at 110 °C. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give a yellow oil 14b (6.5 g).

[0461] MS(ESI) m / z 214.0 [M+H] +

[0462] Step 2: 2-tert-butyl-4-iodothiazole-5-carboxylic acid ethyl ester 14c

[0463] Compound 14b (1 g, 4.6 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (4.6 mL, 1.0 M, 6.9 mmol) was added dropwise at -78 °C under nitrogen protection for 1 h. I₂ (1.78 g, 6.9 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction mixture was cooled to 0 °C, and a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give a yellow oily compound 14c (800 mg).

[0464] MS(ESI) m / z 340.0 [M+H] +

[0465] Step 3: Ethyl 2-tert-butyl-4-phenoxythiazole-5-carboxylate 14 days

[0466] Compound 14c (400 mg, 1.17 mmol) was dissolved in DMF (5 mL), and phenol (166.2 mg, 1.75 mmol), 1,10-phenanthroline (106.2 mg, 0.58 mmol), cuprous iodide (224 mg, 1.75 mmol), and cesium carbonate (765 mg, 2.34 mmol) were added. The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. The reaction solution was cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give a yellow oil 14d (140 mg).

[0467] MS(ESI) m / z 306.0 [M+H] +

[0468] Step 4: 2-tert-butyl-4-iodothiazole-5-carboxylic acid 14e

[0469] Compound 14d (140 mg, 0.46 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (54.9 mg, 2.3 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution to extinguish the reaction, the pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure to give the crude product, which was a yellow oily substance 14e (90 mg).

[0470] MS(ESI) m / z 278.0 [M+H] +

[0471] Step 5 (S,E)-2-tert-butyl-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-4-phenoxythiazol-5-carboxamide 14

[0472] Compound 14e (90 mg, 0.32 mmol) was dissolved in DMF (2 mL), and 7 g (124 mg, 0.35 mmol), DIEA (207 mg, 1.6 mmol), and HATU (370 mg, 0.96 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 14 (87 mg) as a white solid.

[0473] MS(ESI) m / z 435.1 [M+H] +

[0474] 1 H NMR (400MHz, CDCl3) δ7.43-7.37(m,2H),7.25-7.13(m,4H),6.97(dd,J=15.1,4.6Hz,1H),6.46(dd,J=15.1,1.8Hz,1H),4 .19-4.11(m,1H),2.90(s,3H),1.36(s,9H),1.03-0.94(m,1H),0.70-0.62(m,1H),0.61-0.51(m,1H),0.46-0.36(m,2H).

[0475] Example 15 (S,E)-2-cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0476] Step 1: Cyclobutylthioamide 15b

[0477] Compound 15a (500 mg, 5.05 mmol) was dissolved in THF (20 mL), and Lawson's reagent (2.0, 5.05 mmol) and sodium carbonate (535 mg, 5.05 mmol) were added. The mixture was reacted at 70 °C for 3 h under nitrogen protection. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to the crude product, yielding a yellow oily substance 15b (500 mg).

[0478] Step 2: 15c of 2-cyclobutylthiazole-5-carboxylic acid ethyl ester

[0479] Compound 15b (500 mg, 4.76 mmol) was dissolved in acetic acid (5 mL), and ethyl (chloroformyl)acetate (1.52 g, 9.25 mmol) and p-toluenesulfonic acid (17.2 mg, 0.925 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out overnight at 110 °C. The reaction solution was cooled to room temperature, and the acetic acid was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give a yellow oily compound 15c (450 mg).

[0480] MS(ESI) m / z 212.0 [M+H] +

[0481] Step 3: Ethyl 2-cyclobutyl-4-iodothiazole-5-carboxylate 15 days

[0482] Compound 15c (450 mg, 2.13 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (2.2 mL, 1.0 M, 3.19 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. I₂ (812 mg, 3.19 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was carried out overnight at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 49 / 1) to give compound 15d (180 mg), a yellow oil.

[0483] MS(ESI) m / z 337.9 [M+H] +

[0484] Step 4: 2-Cyclobutyl-4-phenoxythiazole-5-carboxylic acid ethyl ester 15e

[0485] Compound 15d (180 mg, 0.534 mmol) was dissolved in DMF (3 mL), and phenol (75.3 mg, 0.801 mmol), 1,10-phenanthroline (48 mg, 0.267 mmol), cuprous iodide (101 mg, 0.534 mmol), and cesium carbonate (347 mg, 1.068 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 100 °C for 3 h. The reaction solution was cooled to room temperature, and water was added to the reaction mixture to extinguish the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 15e (12 mg), a yellow oil.

[0486] MS(ESI) m / z 304.1 [M+H] +

[0487] Step 5: 2-Cyclobutyl-4-phenoxythiazole-5-carboxylic acid 15f

[0488] Compound 15e (12 mg, 0.039 mmol) was dissolved in methanol (0.5 mL) and water (0.25 mL), and lithium hydroxide (4.8 mg, 0.195 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution to extinguish the reaction. The pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give compound 15f (10 mg), a yellow oily substance. The crude product was used directly in the next step.

[0489] MS(ESI) m / z 276.1 [M+H] +

[0490] Step 6 (S,E)-2-cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazole-5-carboxamide 15

[0491] Compound 15f (10 mg, 0.036 mmol) was dissolved in DMF (1 mL), and 7 g of compound (12.5 mg, 0.036 mmol), DIEA (23 mg, 0.18 mmol), and HATU (41.3 mg, 0.108 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 15 (5 mg) as a white solid.

[0492] MS(ESI) m / z 433.0 [M+H] +

[0493] 1 H NMR(400MHz, CDCl3)δ7.41(t,J=8.0Hz,2H),7.24-7.13(m,3H),6.97(dd,J=15 .1,4.5Hz,1H),6.47(dd,J=15.1,1.8Hz,1H),4.19-4.10(m,1H),3.72(p,J=8. 5Hz,1H),2.91(s,3H),2.47-2.37(m,2H),2.31-2.20(m,2H),2.08-1.96(m,2H ),1.02-0.93(m,1H),0.71-0.63(m,1H),0.61-0.54(m,1H),0.46-0.37(m,2H).

[0494] Example 16 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoropropyl)-4-phenoxythiazole-5-carboxamide

[0495] Step 1 1-(4-bromothiazol-2-yl)prop-1-ol 16b

[0496] Compound 16a (9 g, 46.8 mmol) was dissolved in tetrahydrofuran (100 mL), and the reaction system was purged with nitrogen three times. Ethyl magnesium bromide (1 M, 46.8 mL, 93.6 mmol) was added at -78 °C. Under nitrogen protection, the reaction mixture was slowly heated to room temperature for 4 h. The reaction solution was cooled to 0 °C, and a saturated ammonium chloride solution (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give compound 16b (2.7 g), a yellow oil.

[0497] Step 2: 1-(4-bromothiazol-2-yl)prop-1-one 16c

[0498] Compound 16b (2.5 g, 11.3 mmol) was dissolved in dichloromethane (25 mL), and Dysmart reagent (9.6 g, 22.6 mmol) was added. The mixture was reacted overnight at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 16c (1.7 g), a yellow oil.

[0499] Step 3: 4-Bromo-2-(1,1-difluoropropyl)thiazole 16 days

[0500] Compound 16c (1.5 g, 6.8 mmol) was dissolved in dichloromethane (15 mL), and BAST (7.5 g, 34 mmol) was added. The mixture was reacted overnight at room temperature. At 0 °C, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give compound 16d (1.0 g), a yellow oil.

[0501] Step 4: Ethyl 4-bromo-2-(1,1-difluoropropyl)thiazole-5-carboxylate 16e

[0502] Compound 16d (350 mg, 1.4 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (4.3 mL, 1.0 M, 5.2 mmol) was added dropwise at -78 °C. The reaction was carried out under nitrogen protection for 0.5 h. Then, diethyl pyrocarbonate (234 mg, 5.2 mmol) was added dropwise to the reaction mixture, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 16e (400 mg), a yellow oil.

[0503] MS(ESI) m / z 314.1 [M+H] +

[0504] Step 5: 2-(1,1-difluoropropyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 16f

[0505] Compound 16e (200 mg, 0.64 mmol) was dissolved in DMF (5 mL), and potassium phenolate (169.2 mg, 1.28 mmol), 1,10-phenanthroline (28.8 mg, 0.16 mmol), and cuprous iodide (60.8 mg, 0.32 mmol) were added. The reaction system was purged with nitrogen three times and reacted at 100 °C for 2 h. The reaction solution was cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 16f (50 mg), a yellow oil.

[0506] MS(ESI) m / z 327.9 [M+H] +

[0507] Step 6: 16g of 2-(1,1-difluoropropyl)-4-phenoxythiazole-5-carboxylic acid

[0508] 16 g (50 mg, 0.15 mmol) of the compound was dissolved in methanol (1 mL) and water (0.5 mL), and lithium hydroxide (20 mg, 0.75 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to the reaction solution to extinguish the reaction. The pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give 16 g (50 mg) of crude product, a yellow oil.

[0509] MS(ESI) m / z 300.0 [M+H] +

[0510] Step 7 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoropropyl)-4-phenoxythiazole-5-carboxamide 16

[0511] Compound 16 g (50 mg, 0.16 mmol) was dissolved in DMF (1 mL), and 7 g (57.8 mg, 0.16 mmol), DIEA (105.8 mg, 0.48 mmol), and HATU (189 mg, 0.48 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 16 (19.4 mg) as a yellow solid.

[0512] MS(ESI) m / z 457.0 [M+H] +

[0513] 1 H NMR (400MHz, CDCl3) δ7.47-7.39(m,2H),7.30-7.23(m,2H),7.20-7.12(m,2H),6.98(dd,J=15.2,4.7Hz,1H),6.52(dd,J=15.2,1.7Hz,1H),4.20-4.11 (m,1H),2.93(s,3H),2.25(tq,J=16.6,7.5Hz,2H),1.06-0.97(m,1H),1.01 (t,J=7.5Hz,3H),0.75-0.67(m,1H),0.65-0.57(m,1H),0.50-0.38(m,2H).

[0514] Example 17 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-isopropyl-4-phenoxythiazole-5-carboxamide

[0515] Step 1: 2-Isopropylthiazole-5-carboxylic acid ethyl ester 17b

[0516] Compound 17a (1.03 g, 10 mmol) was dissolved in acetic acid (10 mL), and ethyl 2-chloro-2-formyl acetate (1.57 g, 10.5 mmol) and p-toluenesulfonic acid (34 mg, 0.2 mmol) were added. The mixture was reacted at 110 °C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 17b (1.2 g).

[0517] MS(ESI)m / z 200.1[M+H] +

[0518] Step 2: 4-Iodo-2-isopropylthiazole-5-carboxylic acid ethyl ester 17c

[0519] Compound 17b (1.0 g, 5.0 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (7.5 mL, 7.5 mmol, 1.0 M in THF) was added dropwise at -78 °C under nitrogen protection for 1 hour. I₂ (1.9 g, 7.5 mmol) was then dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction mixture. The mixture was then heated to room temperature and reacted for 2 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound 17c (145 mg).

[0520] MS(ESI) m / z 326.0 [M+H] +

[0521] Step 3: Ethyl 2-isopropyl-4-phenoxythiazole-5-carboxylate 17 days

[0522] Compound 17c (145 mg, 0.47 mmol), phenol (84 mg, 0.89 mmol), 1,10-phenanthroline (42 mg, 0.24 mmol), cuprous iodide (89 mg, 0.47 mmol), and cesium carbonate (290 mg, 0.89 mmol) were dissolved in DMF (3 mL). The reaction system was purged with nitrogen three times and reacted at 100 °C for 3 hours. The reaction solution was cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted three times with ethyl acetate (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to obtain compound 17d (12 mg).

[0523] MS(ESI) m / z 292.1 [M+H] +

[0524] Step 4: 2-Isopropyl-4-phenoxythiazole-5-carboxylic acid 17e

[0525] Compound 17d (12 mg, 0.04 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (5 mg, 0.2 mmol) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain compound 17e, which was used directly in the next step.

[0526] MS(ESI) m / z 264.1 [M+H] +

[0527] Step 5: (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)allyl)-2-Isopropyl-4-phenoxythiazole-5-carboxamide 17

[0528] Compound 17e (12 mg, 0.04 mmol) and compound 7 g (17 mg, 0.05 mmol) were dissolved in DMF (2 mL), and HATU (19 mg, 0.05 mmol) and DIEA (16 mg, 0.12 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The collected organic phase was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound 17 (3.6 mg).

[0529] MS(ESI) m / z 421.1 [M+H] +

[0530] 1 H NMR (400MHz, CDCl3) δ7.45-7.38(m,2H),7.26-7.12(m,4H),6.97(dd,J=4.5,15.1Hz,1H),6.48(dd,J=1.8,15.1Hz,1H),4.19-4.12(m,1H ),3.17(p,J=6.8Hz,1H),2.90(s,3H),1.33(d,J=6.8Hz,6H),1.03-0.95(m,1H),0.71-0.62(m,1H),0.63-0.53(m,1H),0.48-0.36(m,2H).

[0531] Example 18 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-methylcyclopropyl)-4-phenoxythiazole-5-carboxamide

[0532] Step 1: 1-Methylcyclopropane-1-thiocarboxamide 18b

[0533] Compound 18a (0.75 g, 7.65 mmol) was dissolved in tetrahydrofuran (20 mL), and Lawson's reagent (3.09 g, 7.65 mmol) and potassium carbonate (0.75 g, 7.65 mmol) were added. The mixture was reacted at 80 °C for 4 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The collected organic phase was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 18b (0.5 g).

[0534] MS(ESI) m / z 115.9 [M+H] +

[0535] Step 2: Ethyl 2-(1-methylcyclopropyl)thiazole-5-carboxylate 18c

[0536] Compound 18b (432 mg, 3.75 mmol) was dissolved in acetic acid (8 mL), and ethyl 2-chloro-2-formyl acetate (568 mg, 3.75 mmol) and p-toluenesulfonic acid (68 mg, 0.4 mmol) were added. The mixture was reacted at 110 °C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound 18c (200 mg).

[0537] MS(ESI) m / z 212.0 [M+H] +

[0538] Step 3: Ethyl 4-iodo-2-(1-methylcyclopropyl)thiazole-5-carboxylate 18 days

[0539] Compound 18c (200 mg, 0.94 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (1.4 mL, 1.4 mmol, 1.0 M in THF) was added dropwise at -78 °C under nitrogen protection for 1 hour. I₂ (359 mg, 1.4 mmol) was then dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction mixture. The mixture was then heated to room temperature and reacted for 2 hours. A saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 18d (170 mg).

[0540] MS(ESI) m / z 337.9 [M+H] +

[0541] Step 4: 2-(1-methylcyclopropyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 18e

[0542] Compound 18d (50 mg, 0.15 mmol), phenol (28 mg, 0.3 mmol), 1,10-phenanthroline (5 mg, 30 μmol), cuprous iodide (3 mg, 15 μmol), and cesium carbonate (97 mg, 0.3 mmol) were dissolved in DMF (2 mL). The reaction system was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction solution was cooled to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to obtain compound 18e (30 mg).

[0543] MS(ESI) m / z 304.0 [M+H] +

[0544] Step 5: 2-(1-Methylcyclopropyl)-4-phenoxythiazole-5-carboxylic acid 18f

[0545] Compound 18e (30 mg, 98 μmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and then lithium hydroxide (7.1 mg, 296 μmol) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain crude product 18f, which was used directly in the next step.

[0546] MS(ESI) m / z 276.0 [M+H] +

[0547] Step 6 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-methylcyclopropyl)-4-phenoxythiazole-5-carboxamide 18

[0548] Compound 18f (28 mg, 0.1 mmol) and compound 7g (42 mg, 0.12 mmol) were dissolved in DMF (5 mL), and HATU (46 mg, 0.12 mmol) and DIEA (42 mg, 0.3 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was then purified by preparative HPLC to obtain compound 18 (18.3 mg).

[0549] MS(ESI) m / z 433.0 [M+H] +

[0550] 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.2Hz,1H),7.43-7.37(m,2H),7.21-7.12(m,3H),6.83(dd,J=15.3,5.3Hz,1H),6.73(dd,J=15.3,1.2Hz,1H ),4.03-3.96(m,1H),2.97(s,3H),1.46(s,3H),1.15-1.10(m,3H),1.06 -1.00(m,2H),0.57-0.47(m,1H),0.46-0.32(m,2H),0.30-0.22(m,1H).

[0551] Example 19 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(2-hydroxypropyl-2-yl)-4-phenoxythiazol-5-carboxamide

[0552] Step 1 2-(tert-butyldimethylsiloxy)-2-methylpropionamide 19b

[0553] Compound 19a (7.8 g, 75.7 mmol) was dissolved in dichloromethane (80 mL), and 2,6-dimethylpyridine (16.2 g, 151 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (24 g, 90.8 mmol) were added under ice bath conditions. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (150 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 3). The collected organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain compound 19b (7.8 g).

[0554] Step 2: 2-(tert-butyldimethylsiloxy)-2-methylpropionylthioamide 19c

[0555] Compound 19b (7.8 g, 36 mmol) was dissolved in tetrahydrofuran (80 mL), and Lawson's reagent (14.5 g, 36 mmol) and potassium carbonate (4.9 g, 36 mmol) were added. The mixture was reacted at 70 °C for 4 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The collected organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 19c (4.9 g).

[0556] MS(ESI)m / z 234.0[M+H]+

[0557] Step 3: Ethyl 2-(2-hydroxypropyl-2-yl)thiazole-5-carboxylate 19d

[0558] Compound 19c (4.9 g, 20.9 mmol) was dissolved in acetic acid (49 mL), and ethyl 2-chloro-2-formyl acetate (3.14 g, 20.9 mmol) and p-toluenesulfonic acid (340 mg, 2.09 mmol) were added. The mixture was reacted at 110 °C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 19d (2.3 g).

[0559] MS(ESI) m / z 216.0 [M+H] +

[0560] Step 4: Ethyl 2-(2-((tert-butyldimethylsiloxy)prop-2-yl)thiazolyl-5-carboxylate 19e

[0561] Compound 19d (2.07 g, 9.49 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (2.84 g, 28.5 mmol) and 4-dimethylaminopyridine (118 mg, 0.95 mmol) were added under ice bath conditions, followed by tert-butyldimethylsilyltrifluoromethanesulfonate (3.76 g, 14.25 mmol). The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 19e (1.84 g).

[0562] MS(ESI) m / z 330.1 [M+H] +

[0563] Step 5: 2-(2-((tert-butyldimethylsiloxy)prop-2-yl)-4-iodothiazol-5-carboxylic acid ethyl ester 19f

[0564] Compound 19e (1.84 g, 6.0 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (12 mL, 12 mmol, 1.0 M in THF) was added dropwise at -78 °C under nitrogen protection for 1 hour. I₂ (4.57 g, 18 mmol) was then dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction mixture. The mixture was heated to room temperature and reacted for 2 hours. A saturated ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound 19f (750 mg), a yellow oily liquid.

[0565] MS(ESI) m / z 456.0 [M+H] +

[0566] Step 6: 19g of 2-(2-hydroxypropyl-2-yl)-4-phenoxythiazol-5-carboxylic acid ethyl ester

[0567] Compound 19f (455 mg, 1.0 mmol), phenol (282 mg, 3.0 mmol), 1,10-phenanthroline (38 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), and cesium carbonate (960 mg, 3.0 mmol) were added to DMF (4 mL). The reaction system was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction solution was cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to obtain compound 19 g (60 mg).

[0568] MS(ESI) m / z 308.1 [M+H] +

[0569] Step 7: 2-(2-hydroxypropyl-2-yl)-4-phenoxythiazol-5-carboxylic acid (19h)

[0570] 19 g (33 mg, 0.1 mmol) of compound was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and then lithium hydroxide (13 mg, 0.5 mmol) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure, and the pH was adjusted to 1 by adding 1 M hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound 19h. The crude product was used directly in the next step.

[0571] MS(ESI) m / z 280.0 [M+H]+

[0572] Step 8 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(2-hydroxypropyl-2-yl)-4-phenoxythiazol-5-carboxamide 19

[0573] Compound 19h (28 mg, 0.1 mmol) and compound 7g (38 mg, 0.11 mmol) were dissolved in DMF (2 mL), and HATU (42 mg, 0.11 mmol) and DIEA (43 mg, 0.33 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The collected organic phase was concentrated to obtain the crude product, which was then purified by preparative HPLC to obtain compound 19 (21.2 mg).

[0574] MS(ESI) m / z 437.0 [M+H] +

[0575] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.2Hz,1H),7.44-7.38(m,2H),7.22-7.12(m,3H),6.84(dd,J=15.2,5.2Hz,1H),6.74(dd,J=15.2,1.2Hz,1 H),6.21(brs.,1H),4.06-3.96(m,1H),2.97(s,3H),1.42(s,6H),1.21 -1.10(m,1H),0.56-0.48(m,1H),0.46-0.32(m,2H),0.30-0.22(m,1H).

[0576] Example 20 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-(difluoromethyl)cyclopropyl)-4-phenoxythiazole-5-carboxamide

[0577] Step 1: 1-(tert-butyldiphenylsiloxanemethyl)cyclopropane-1-carboxylic acid ethyl ester 20b

[0578] Compound 20a (5.0 g, 34.68 mmol) was dissolved in DCM (60 mL), and imidazole (4.72 g, 69.36 mmol) and TBDPSCl (10.49 g, 38.15 mmol) were added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, water (200 mL) was added, and the mixture was extracted three times with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether) to give colorless liquid 20b (12.0 g).

[0579] MS(ESI) m / z 305.1 [M-Ph] +

[0580] Step 2: 1-(tert-butyldiphenylsiloxomethyl)cyclopropane-1-carboxylic acid 20c

[0581] Compound 20b (12.0 g, 31.37 mmol) was dissolved in methanol (100 mL), and lithium hydroxide (2.25 g, 94.10 mmol) was dissolved in water (10 mL) and added to the above reaction solution. The reaction was carried out at room temperature for 18 hours. After the reaction was completed, the pH was adjusted to 7 with citric acid, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure to give compound 20c (12.0 g), a white solid. The crude product was used directly in the next step.

[0582] MS(ESI) m / z 277.0 [M-Ph] +

[0583] Step 3: 1-(tert-butyldiphenylsiloxomethyl)cyclopropane-1-formamide 20d

[0584] Compound 20c (12.0 g, crude) was dissolved in DMF (120 mL), and ammonium chloride (9.05 g, 169.24 mmol), DIEA (13.12 g, 101.55 mmol), and HATU (19.31 g, 50.77 mmol) were added. The reaction was carried out at room temperature for 18 hours. After the reaction was completed, water was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give compound 20d (10.5 g), a white solid.

[0585] MS(ESI) m / z 276.0 [M-Ph] +

[0586] Step 4: 1-(tert-butyldiphenylsiloxomethyl)cyclopropane-1-thiocarboxamide 20e

[0587] Compound 20d (5.5 g, 15.56 mmol) was dissolved in THF (60 mL), and Lawson's reagent (3.15 g, 7.78 mmol) was added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, water was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to give compound 20e (5.0 g), a white solid.

[0588] MS(ESI) m / z 292.0 [M-Ph] +

[0589] Step 5: 20f of 2-(1-(acetoxymethyl)cyclopropyl)thiazole-5-carboxylic acid ethyl ester

[0590] Compound 20e (3.0 g, 8.12 mmol) was dissolved in acetic acid (30 mL), and PTSA (0.28 g, 1.62 mmol) and ethyl (chloroformyl)acetate (2.44 g, 16.23 mmol) were added. The reaction was carried out at 110 °C for 18 h. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 20f (300 mg), a yellow oil.

[0591] MS(ESI) m / z 270.0 [M+H] +

[0592] Step 6: 20g of 2-(1-(hydroxymethyl)cyclopropyl)-4-iodothiazole-5-carboxylic acid ethyl ester

[0593] Compound 20f (350 mg, 15.87 mmol) was dissolved in THF (5 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (3.9 mL, 1.0 M, 3.90 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. I₂ (0.99 g, 3.90 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was carried out at room temperature for 18 h. After the reaction was complete, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride at low temperature, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 20 g (40 mg) of a yellow oil.

[0594] MS(ESI) m / z 353.9 [M+H] +

[0595] Step 7: 2-(1-(hydroxymethyl)cyclopropyl)-4-phenoxythiazol-5-carboxylic acid ethyl ester for 20 hours

[0596] 20 g (30 mg, 0.085 mmol) of compound was dissolved in DMF (1 mL), and phenol (24 mg, 0.25 mmol), 1,10-phenanthroline (3 mg, 0.017 mmol), cuprous iodide (3.2 mg, 0.017 mmol), and cesium carbonate (83 mg, 0.25 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 90 °C for 18 h. The reaction solution was cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, and the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound 20 h (24 mg), a yellow oil.

[0597] MS(ESI) m / z 320.1 [M+H] +

[0598] Step 8: 2-(1-Formylcyclopropyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 20i

[0599] Compound 20h (20 mg, 0.063 mmol) was dissolved in DCM (1 mL), and DMP (40 mg, 0.94 mmol) was added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain compound 20i (13 mg).

[0600] MS(ESI) m / z 318.0 [M+H] +

[0601] Step 9: 2-(1-(difluoromethyl)cyclopropyl)-4-phenoxythiazol-5-carboxylic acid ethyl ester 20j

[0602] Compound 20i (13 mg, 0.041 mmol) was dissolved in DCM (1 mL), and BAST (14 mg, 0.061 mmol) was added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was extracted with DCM. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 20j (10.0 mg).

[0603] MS(ESI) m / z 340.0 [M+H] +

[0604] Step 10: 2-(1-(difluoromethyl)cyclopropyl)-4-phenoxythiazol-5-carboxylic acid 20kJ

[0605] Compound 20j (10 mg, 0.029 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), and lithium hydroxide (2.12 mg, 0.088 mmol) was added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product, compound 20k (9.0 mg), a white solid. The crude product was used directly for the next step.

[0606] MS(ESI) m / z 312.0 [M+H] +

[0607] Step 11 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-(difluoromethyl)cyclopropyl)-4-phenoxythiazol-5-carboxamide 20

[0608] Compound 20k (9.0 mg, crude) was dissolved in DMF (2 mL), and 7 g of compound (14.3 mg, 0.043 mmol), DIEA (11.2 mg, 0.87 mmol), and HATU (16.5 mg, 0.043 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 20 (1.4 mg), a white solid.

[0609] MS(ESI) m / z 469.1 [M+H] +

[0610] 1 H NMR(400MHz,CDCl3)δ7.46-7.36(m,2H),7.20 -7.12(m,3H),6.97(dd,J=15.2,4.6Hz,1H),6.49(dd,J=15.2,1.8Hz,1H),6.12(t,J=56.7Hz,1H),4.19-4.09(m,1H),2.92 (s,3H),1.71-1.61(m,2H),1.46-1.38(m,2H),1.01-0.96(m,1H),0.73-0.63(m,1H),0.63-0.54(m,1H),0.46-0.37(m,2H) .

[0611] 19 F NMR (376MHz, CDCl3) δ-120.29.

[0612] Example 21 (R,E)-2-(1,1-difluoroethyl)-N-(1-methoxy-4-(methanesulfonyl)but-3-en-2-yl)-4-phenoxythiazolyl-5-carboxamide

[0613] The synthesis of (R,E)-1-methoxy-4-(methylsulfonyl)but-3-ene-2-amine p-toluenesulfonate (21a) was performed according to patent WO2024010782. Compounds 5f (40 mg, 0.14 mmol) and 21a (59 mg, 0.17 mmol) were dissolved in DMF (1 mL), and HATU (80 mg, 0.21 mmol) and DIEA (38 mg, 0.28 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by preparative HPLC to obtain compound 21 (22 mg), a white solid.

[0614] MS(ESI) m / z 447.0 [M+H]+

[0615] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.4Hz,1H),7.42(t,J=8.0Hz,2H),7.25-7.22(m,1H),7.18(d,J=7.6Hz,2H),6.97-6.92(dd,J=15.2,4 .8Hz,1H),6.54-6.50(dd,J=15.2,1.6Hz,1H),4.99-4.96(m,1H),3.63-3.55(m,2H),3.31(s,3H),2.91(s,3H),1.98(t,J=18.4Hz,3H).

[0616] Example 22 (S,E)-N-(1-cyclobutyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxamide

[0617] The synthesis of compound (S,E)-1-cyclobutyl-3-(methanesulfonyl)prop-2-en-1-amine p-toluenesulfonate (22a) was performed according to patent WO2024010782. Compound 5f (40 mg, 0.14 mmol) and 22a (61 mg, 0.17 mmol) were dissolved in DMF (1 mL), and HATU (80 mg, 0.21 mmol) and DIEA (38 mg, 0.28 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain compound 22 (22 mg), a white solid.

[0618] MS(ESI) m / z 457.1 [M+H] +

[0619] 1H NMR(400MHz, CDCl3) δ7.42(4,J=8.0Hz,2H),7.26(d,J=14.8Hz,1H),7.14(d,J= 7.6Hz,2H),7.07(d,J=8.0Hz,1H),6.84-6.79(dd,J=15.2,5.2Hz,1H),6.48-6.4 4(dd,J=15.2,1.6Hz,1H),4.79-4.73(m,1H),2.90(s,3H),2.55-2.49(m,1H),2 .12-1.98(m,2H),1.96(t,J=18.4Hz,3H),1.89-1.86(m,2H),1.84-1.77(m,2H).

[0620] Example 23 (S,E)-N-(1-cyclobutyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxamide

[0621] Compounds 12b (60 mg, 0.2 mmol) and 22a (86 mg, 0.24 mmol) were dissolved in DMF (1 mL), and HATU (152 mg, 0.4 mmol) and DIEA (82 mg, 0.6 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The collected organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to give compound 23 (35 mg) as a white solid.

[0622] MS(ESI) m / z 476.1 [M+H] +

[0623] 1 H NMR (400MHz, CDCl3) δ8.13 (d, J = 4.8Hz, 1H), 7.97-7.92 (m, 1H), 7.33-7.30 (d d,J=8.0,3.2Hz,1H),6.97(d,J=8.0Hz,1H),6.87-6.82(dd,J=15.2,5.2Hz,1 H),6.55-6.51(dd,J=15.2,1.6Hz,1H),4.83-4.78(m,1H),2.94(s,3H),2.60 -2.54(m,1H),2.15-2.07(m,2H),1.95(t,J=18.4Hz,3H),1.91-1.83(m,4H).

[0624] Example 24 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((2-methylpyridin-3-yl)oxy)thiazolyl-5-carboxamide

[0625] Compound 24 was synthesized with reference to Example 10, by replacing m-fluorophenol with the intermediate 2-methylpyridine-3-phenol (24a) to obtain compound 24.

[0626] MS(ESI) m / z 458.1 [M+H] +

[0627] 1 H NMR (400MHz, CDCl3) δ8.46-8.44 (dd, J=4.8, 1.6Hz, 1H), 7.50-7.48 (dd, J=8.4, 1. 6Hz,1H),7.27-7.22(m,2H),7.01-6.96(dd,J=15.2,4.8Hz,1H),6.59-6.55(dd,J= 15.2,2.0Hz,1H),4.17-4.11(m,1H),2.95(s,3H),2.54(s,3H),1.92(t,J=18.4Hz ,3H),1.08-1.02(m,1H),0.77-0.71(m,1H),0.68-0.63(m,1H),0.51-0.42(m,2H).

[0628] Example 25 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoropropyl)-4-[(2-fluoropyridin-3-yl)oxy]thiazole-5-carboxamide

[0629] Compound 25 was synthesized according to Example 16, by replacing m-fluorophenol with 2-fluoro-3-hydroxypyridine to obtain compound 25.

[0630] MS(ESI) m / z 476.1 [M+H] +

[0631] 1H NMR (400MHz, CDCl3) δ8.15-8.10(m,1H),8.02-7.94(m,1H),7.32(dd,J=7.9,4.8Hz,1H),7.22(d,J=7.6Hz,1H),7.01(dd,J=15.2,4.8Hz,1H),6.59(dd, J=15.2,1.7Hz,1H),4.23-4.12(m,1H),2.97(s,3H),2.33-2.16(m,2H),1.1 4-1.01(m,1H),1.02(t,J=7.5Hz,3H),0.80-0.63(m,2H),0.55-0.42(m,2H).

[0632] Example 26 (R,E)-2-(1,1-difluoropropyl)-N-(1-methoxy-4-(methanesulfonyl)but-3-en-2-yl)-4-phenoxythiazolyl-5-carboxamide

[0633] Compound 16 g (18 mg, 0.06 mmol) was dissolved in DMF (1 mL), and compound 21a (32.1 mg, 0.09 mmol), DIEA (38.5 mg, 0.18 mmol), and HATU (68.6 mg, 0.30 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 26 (2.0 mg), a white solid.

[0634] MS(ESI) m / z 461.1 [M+H] +

[0635] 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 8.1Hz, 1H), 7.45-7.39 (m, 2H), 7.25-7.22 (m ,1H),7.20-7.15(m,2H),6.95(dd,J=15.1,5.0Hz,1H),6.53(dd,J=15.1,1.7 Hz,1H),5.02-4.94(m,1H),δ3.61(dd,J=9.5,3.4Hz,1H),3.57(dd,J=9.5,4. 1Hz,1H),3.31(s,3H),2.91(s,3H),2.36-2.19(m,2H),1.03(t,J=7.5Hz,3H).

[0636] Example 27 (S,E)-4-((2-chloropyridin-3-yl)oxy)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)thiazole-5-carboxamide

[0637] Compound 27 was synthesized according to Example 10, by replacing m-fluorophenol with 2-chloro-3-hydroxypyridine (27a) to obtain compound 27.

[0638] MS(ESI) m / z 478.0 [M+H] +

[0639] 1 H NMR (400MHz, CDCl3) δ8.35(dd,J=4.7,1.6Hz,1H),7.92(dd,J=8.1,1.6Hz,1H),7.40(dd,J=8.1,4.7Hz,2H),7.01(dd,J=15.2,4.7Hz,1H),6.59(dd,J= 15.2,1.7Hz,1H),4.22-4.12(m,1H),2.96(s,3H),1.97(t,J=18.3Hz,3H),1 .14-1.01(m,1H),0.81-0.71(m,1H),0.70-0.62(m,1H),0.56-0.41(m,2H).

[0640] 19 F NMR (376MHz, CDCl3) δ -84.46.

[0641] Example 28 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-fluorocyclopentyl)-4-phenoxythiazole-5-carboxamide

[0642] Step 1: 2-(1-hydroxycyclopentyl)thiazole-5-carboxylic acid ethyl ester 28c

[0643] Compound 28a (3 g, 12.7 mmol) was dissolved in DCM (30 mL), and the reaction system was purged with nitrogen three times. Butyllithium (2.5 M, 5.6 mL, 13.9 mmol) was added at -78 °C, and the reaction was allowed to proceed for 1 h. Then, compound 28b (1.2 g, 15.2 mmol) was added, and the temperature was raised from -78 °C to room temperature for 4 h. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction mixture under ice bath conditions, followed by extraction with ethyl acetate. The organic phases were combined, concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to give a yellow oily substance 28c (2.6 g).

[0644] MS(ESI) m / z 226.0 [M-OH] +

[0645] Step 2: Ethyl 2-(1-fluorocyclopentyl)thiazole-5-carboxylate 28 days

[0646] Compound 28c (1 g, 4.1 mmol) was dissolved in dichloromethane (10 mL), and DAST (1.33 g, 8.2 mmol) was added dropwise at -78 °C. The reaction mixture was allowed to react overnight at room temperature. Under ice bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution at 0 °C, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow oily substance 28d (800 mg).

[0647] MS(ESI) m / z 243.9 [M+H] +

[0648] Step 3: 2-(1-Fluorocyclopentyl)-4-iodothiazole-5-carboxylic acid 28e

[0649] Compound 28d (400 mg, 1.65 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (4.95 mL, 1.0 M, 4.95 mmol) was added dropwise at -78 °C under nitrogen protection for 1 h. Then, I2 (1.2 g, 4.95 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction mixture under ice bath conditions, followed by extraction with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 28e (200 mg), a yellow oil.

[0650] MS(ESI)m / z 370[M+H] +

[0651] Step 4: 2-(1-Fluorocyclopentyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 28f

[0652] Compound 28e (200 mg, 0.54 mmol) was dissolved in DMF (5 mL), and phenol (101.5 mg, 1.08 mmol), 1,10-phenanthroline (19.4 mg, 0.108 mmol), and cuprous iodide (20.5 mg, 0.108 mmol) were added. The reaction system was purged with nitrogen three times. Under nitrogen protection, the reaction was carried out at 90 °C for 2 h. The reaction solution was cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow oily substance 28f (100 mg).

[0653] MS(ESI) m / z 336.0 [M+H] +

[0654] Step 5: 28g of 2-(1-fluorocyclopentyl)-4-phenoxythiazole-5-carboxylic acid

[0655] Compound 28f (100 mg, 0.29 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (34.8 mg, 1.45 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution, the pH was adjusted to 4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give compound 28 (60 mg) as a colored oil. The crude product was used directly in the next step.

[0656] MS(ESI) m / z 307.0 [M+H] +

[0657] Step 6 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-fluorocyclopentyl)-4-phenoxythiazol-5-carboxamide 28

[0658] Compound 28 g (60 mg, 0.19 mmol) was dissolved in DMF (1 mL), and 7 g (135.6 mg, 0.38 mmol), DIEA (184.1 mg, 0.77 mmol), and HATU (222.8 mg, 0.57 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative HPLC to obtain compound 28 (40 mg) as a yellow solid.

[0659] MS(ESI) m / z 465.1 [M+H] +

[0660] 1 H NMR (400MHz, CDCl3) δ7.45-7.37(m,2H),7.25-7.16(m,2H),7.16-7.10(m,2H),6.97(dd,J=15.1,4.6Hz,1H),6.48(dd,J=15.1,1.8Hz,1H),4.2 0-4.11(m,1H),2.91(s,3H),2.27-2.07(m,4H),1.97-1.82(m,4H),1.04 -0.92(m,1H),0.73-0.63(m,1H),0.62-0.52(m,1H),0.48-0.35(m,2H).

[0661] 19 F NMR (376MHz, CDCl3) δ-139.19.

[0662] Example 29 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide

[0663] The synthesis of compound 29 is described in Example 12, where intermediate 29a was used to replace compound 9e to obtain compound 29.

[0664] MS(ESI) m / z 488.1 [M+H] +

[0665] 1 H NMR (400MHz, CDCl3) δ8.15-8.09(m,1H),8.06-8.00(m,1H),7.32(dd,J=8.0,4.8Hz,1H),7.24(s,1H),7.01(dd,J=15.2,4.8Hz,1H),6.6 0(dd,J=15.2,1.7Hz,1H),4.23-4.14(m,1H),2.97(s,3H),1.71-1.57(m,1H),1.15-1.02(m,1H),0.85-0.64(m,6H),0.54-0.41(m,2H).

[0666] Example 30N-((1S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoro-3-methoxypropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxamide

[0667] The synthesis of compound 30 is described in Example 12, where intermediate 30a was used to replace compound 9e to obtain compound 30.

[0668] MS(ESI) m / z 506.1 [M+H] +

[0669] 1 H NMR (400MHz, CDCl3) δ8.12 (dt, J=4.9, 1.6Hz, 1H), 7.97 (ddd, J=9.6, 8.0, 1.6Hz, 1H), 7.31(dd,J=8.0,4.8Hz,1H),7.23(d,J=7.6Hz,1H),7.00(dd,J=15.2,4.8Hz,1H),6.5 9(dd,J=15.2,1.6Hz,1H),4.21-4.11(m,1H),3.54(t,J=6.5Hz,2H),3.25(s,3H),2.9 7(s,3H),2.62-2.47(m,2H),1.14-1.01(m,1H),0.81-0.62(m,2H),0.55-0.41(m,2H).

[0670] Example 31: N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoropyridin-3-yl)oxy)-2-(2-methylcyclopropyl)thiazolyl-5-carboxamide

[0671] Compound 31 was synthesized according to Example 13, by replacing potassium phenolate with 2-fluoro-3-hydroxypyridine to obtain compound 31.

[0672] MS(ESI) m / z 452.1 [M+H] +

[0673] 1 H NMR(400MHz, CDCl3)δ8.09-8.08(m,1H),7.97-7.93(m,1H),7.30-7.27(m,1H),7.13–7.11(m,1H),7.04–6.99(m,1H),6.60-6 .55(m,1H),4.18-4.13(m,1H),2.97(s,3H),2.04–2.01(m,1H),1.92-1.88(m,1H),1.40-1.35(m,1H),1.32–1.18(m,3H),1.08 -1.02(m,2H),0.75-0.64(m,2H),0.51-0.42(m,2H).

[0674] Example 32N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(2,2-difluorocyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxamide

[0675] The synthesis of compound 32 is described in Example 12, where intermediate 32a is used to replace compound 9e to obtain compound 32.

[0676] MS(ESI) m / z 474.0 [M+H] +

[0677] 1H NMR (400MHz, CDCl3) δ8.11(d,J=4.8Hz,1H),7.99-7.92(m,1H),7.30(dd,J=8.0,4.8Hz,1H),7.16(d,J=7.6Hz,1H),7.05-6.97(m,1H),6.62- 6.54(m,1H),4.19-4.10(m,1H),3.02-2.92(m,1H),2.96(s,3H),2.09- 1.94(m,2H),1.11-1.01(m,1H),0.78-0.62(m,2H),0.54-0.39(m,2H).

[0678] Example 33 (S,E)-4-(2-cyanophenoxy)-N-1-(cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)thiazole-5-carboxamide

[0679] Compound 33 was synthesized according to Example 12, by replacing 2-fluoro-3-hydroxypyridine with o-hydroxybenzonitrile to obtain compound 33.

[0680] MS(ESI) m / z 468.1 [M+H] +

[0681] 1 H NMR (400MHz, CDCl3) δ7.73 (dd, J=7.9, 1.6Hz, 1H), 7.72-7.67 (m, 1H), 7.61 (dd, J=8.5,1.1Hz,1H),7.38(td,J=7.6,1.1Hz,1H),7.29-7.27(m,1H),7.02(dd,J=1 5.2,4.7Hz,1H),6.64(dd,J=15.2,1.7Hz,1H),4.25-4.11(m,1H),2.96(s,3H),2 .00(t,J=18.3Hz,3H),1.19-1.10(m,1H),0.79-0.62(m,2H),0.54-0.41(m,2H).

[0682] Example 34 N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-cyclopropylethyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxamide

[0683] The synthesis of compound 34 is described in Example 12, where compound 9e was replaced with compound 34a to obtain compound 34.

[0684] MS(ESI)m / z 466.1[M+H]+

[0685] 1 H NMR(400MHz, CDCl3)δ8.08(dt,J=4.8,1.6Hz,1H),8.04-7.99(m,1H),7.28(dd,J=8.0,4 .8Hz,1H),7.19(d,J=7.6Hz,1H),7.02(dd,J=15.1,4.6Hz,1H),6.58(dd,J=15.1,1.7Hz ,1H),4.21-4.11(m,1H),2.96(s,3H),2.27-2.19(m,1H),1.38(d,J=7.0Hz,3H),1.11-1 .02(m,1H),1.01-0.91(m,1H),0.79-0.57(m,4H),0.54-0.39(m,2H),0.39-0.23(m,2H).

[0686] Example 35 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)enyl)-4-(2-fluoropyridine-3-ether)-2-(2-tert-methyl-3-yn-2-yl)thiazolyl-5-carboxamide

[0687] Step 1: Diethyl 2-(4-chlorothiazol-2-yl)malonate 35a

[0688] Compound 9a (30.0 g, 195 mmol) was dissolved in DMF (300 mL), and diethyl malonate (31.51 g, 196.74 mmol) and cesium carbonate (95.20 g, 292.19 mmol) were added. The mixture was reacted at 80 °C for 3 h. After the reaction was complete, water (200 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give compound 35a (45.0 g), a yellow liquid.

[0689] MS(ESI) m / z 278.1 [M+H] +

[0690] Step 2: ethyl 2-(4-chlorothiazo-2-yl)acetate 35b

[0691] Compound 35a (12.0 g, 43.21 mmol) was dissolved in DMSO (100 mL), and lithium chloride (2.20 g, 51.85 mmol) was added. The reaction was carried out at 120 °C for 18 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give compound 35b (2.59 g), a yellow liquid.

[0692] MS(ESI) m / z 205.9 [M+H] +

[0693] Step 3: Ethyl 2-(4-chlorothiazol-2-yl)-2-methylpropionate 35c

[0694] Compound 35b (2.59 g, 12.59 mmol) was dissolved in DMF (30 mL). After cooling to 0°C, sodium hydride (1.51 g, 37.78 mmol, 60% purity) was added. The mixture was reacted at 0°C for 0.5 hours, followed by the addition of iodomethane (5.36 g, 37.78 mmol), and the reaction was continued for another 2.5 hours. After the reaction was complete, water was added to the mixture, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give compound 35c (2.0 g).

[0695] MS(ESI) m / z 234.0 [M+H] +

[0696] Step 4: 2-(4-chlorothiazo-2-yl)-2-methyl-1-propanol 35d

[0697] Compound 35c (1.6 g, 6.88 mmol) was dissolved in DCM (20 mL), cooled to 0 °C, and then DIBAL-H (20.54 mL, 20.54 mmol) was added. The mixture was then slowly heated to 25 °C and reacted for 18 h. After the reaction was complete, a saturated aqueous solution of potassium sodium tartrate was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 35d (1.0 g).

[0698] MS(ESI) m / z 191.9 [M+H] +

[0699] Step 5: 2-(4-chlorothiazol-2-yl)-2-methylpropanol acetate 35e

[0700] Compound 35d (1.0 g, 5.22 mmol) was dissolved in DCM (10 mL), and acetic anhydride (0.58 g, 5.74 mmol) and TEA (0.58 g, 5.74 mmol) were added. The mixture was reacted at 25 °C for 18 h. After the reaction was complete, the reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 35e (900 mg).

[0701] MS(ESI) m / z 234.0 [M+H] +

[0702] Step 6: 2-(1-acetyl-2-methylpropanol)-4-chlorothiazol-5-carboxylic acid ethyl ester 35f

[0703] Compound 35f (1.2 g, 5.13 mmol) was dissolved in THF (15 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (10.27 mL, 1.0 M, 10.27 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. Diethyl pyrocarbonate (1.67 g, 10.27 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. After the addition was complete, the mixture was heated to room temperature and reacted for 18 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice bath conditions, followed by extraction with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 35f (300 mg).

[0704] MS(ESI) m / z 306.0 [M+H] +

[0705] Step 7: 35g of 2-(1-acetyl-2-methylpropanol)-4-((2-fluoropyridine-3-ether)thiazole-5-carboxylic acid ethyl ester

[0706] Compound 35f (5.0 g, 16.35 mmol) was dissolved in DMF (50 mL), and 2-fluoro-3-hydroxypyridine (2.77 g, 24.53 mmol) and cesium carbonate (10.66 g, 32.70 mmol) were added. The reaction mixture was reacted at room temperature for 18 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to give compound 35 g (2.0 g).

[0707] MS(ESI) m / z 383.1 [M+H] +

[0708] Step 8: 4-((2-fluoropyridine-3-ether)-2-(1-hydroxy-2-methylpropanol)thiazole-5-carboxylate methyl ester for 35 hours

[0709] 35 g (1.0 g, 2.62 mmol) of compound was dissolved in methanol (15 mL), and potassium carbonate (1.81 g, 13.08 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound 35 h (600 mg).

[0710] MS(ESI) m / z 327.1 [M+H] +

[0711] Step 9: 4-((2-fluoropyridine-3-ether)-2-(2-methyl-1-propanal)thiazole-5-carboxylic acid methyl ester 35i

[0712] Compound 35h (600.0 mg, 1.76 mmol) was dissolved in DCM (1 mL), and DMP (1.50 g, 3.53 mmol) was added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was extracted with DCM. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 35i (400.0 mg).

[0713] MS(ESI) m / z 325.0 [M+H] +

[0714] Step 10: 4-((2-fluoropyridine-3-ether)-2-(2-methyl-1-propynyl)thiazole-5-carboxylic acid methyl ester 35j

[0715] Compound 35i (400 mg, 1.18 mmol) was dissolved in methanol, and potassium carbonate (495 mg, 3.55 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (272 mg, 1.42 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 35j (15.0 mg).

[0716] MS(ESI) m / z 321.0 [M+H] +

[0717] Step 11 4-((2-fluoropyridine-3-ether)-2-(2-methyl-1-propynyl)thiazolyl-5-carboxylic acid 35k

[0718] Compound 35j (15.0 mg, 0.047 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), and lithium hydroxide (5.61 mg, 0.23 mmol) was added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 35k (15.0 mg, crude). The crude product was used directly for the next step.

[0719] MS(ESI) m / z 307.0 [M+H] +

[0720] Step 12 (S,E)-N-(1-Cyclopropyl-3-(Methylsulfonyl)enyl)-4-(2-Fluoropyridine-3-ether)-2-(2-tert-methyl-3-yn-2-yl)thiazolyl-5-carboxamide 35

[0721] Compound 35k (15.0 mg, crude) was dissolved in DMF (1 mL), and 7 g of compound 35k (24.0 mg, 0.073 mmol), DIEA (19.0 mg, 0.15 mmol), and HATU (28.0 mg, 0.073 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered, and compound 35k (7.6 mg) was obtained as a white solid by HPLC.

[0722] MS(ESI) m / z 464.1 [M+H] +

[0723] 1 H NMR (400MHz, CDCl3) δ8.14-8.11(m,1H),8.07-8.02(m,1H),7.33(dd,J=7.9,4.8Hz,1H),7.22(d,J=7.5Hz,1H),7.05(dd,J=15.2,4.6Hz,1H),6.62(dd ,J=15.2,1.7Hz,1H),4.28–4.11(m,1H),3.00(s,3H),2.49(s,1H),1.65(s, 3H),1.64(s,3H),1.13-1.07(m,1H),0.80-0.69(m,2H),0.55-0.47(m,2H).

[0724] Example 36 N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide

[0725] Step 1: Ethyl 4-chloro-2-((1S,2S)-2-(difluoromethyl)cyclopropyl)thiazol-5-carboxylate 36b

[0726] The synthesis of compound 36a is based on patent WO2022 / 68929A1. Compounds 32a-4 (500 mg, 2.21 mmol) and 36a (579 mg, 2.65 mmol) were dissolved in 1,4-dioxane (5 mL), and Pd(dppf)Cl2 (162 mg, 0.22 mmol), H2O (1 mL), and K2CO3 (611 mg, 4.42 mmol) were added. After purging three times with argon, the reaction was carried out at 85 °C for 18 h. After the reaction was complete, the mixture was concentrated under reduced pressure to a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to give compound 36b (270 mg), a yellow solid.

[0727] MS(ESI) m / z 282.0 [M+H] +

[0728] Step 2: Ethyl 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazole-5-carboxylate 36c

[0729] Compound 36b (50.0 mg, 0.18 mmol) was dissolved in DMF (1 mL), and 2-fluoro-3-hydroxypyridine (60.2 mg, 0.53 mmol) and cesium carbonate (547 mg, 1.68 mmol) were added. The mixture was reacted at 80 °C for 14 hours. After the reaction was complete, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 36c (20.0 mg).

[0730] MS(ESI) m / z 359.0 [M+H] +

[0731] Step 3: 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxylic acid 36d

[0732] Compound 36c (20.0 mg, 0.06 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), and lithium hydroxide (4.0 mg, 0.18 mmol) was added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 36d (20.0 mg). The crude product was used directly for the next step.

[0733] MS(ESI) m / z 331.0 [M+H] +

[0734] Step 4: N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide 36

[0735] Compound 36d (20.0 mg, crude) was dissolved in DMF (1 mL), and 7 g of compound 36d (30 mg, 0.09 mmol), DIEA (23.5 mg, 0.18 mmol), and HATU (35 mg, 0.09 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and compound 36 (7.7 mg) was obtained as a pale yellow solid by HPLC.

[0736] MS(ESI) m / z 488.1 [M+H] +

[0737] 1 H NMR (400MHz, CDCl3) δ8.11 (dd, J=4.8, 1.6Hz, 1H), 7.90 (ddd, J=9.6, 8.0, 1.6Hz, 1H), 7.29 (dd, J= 8.0,4.8Hz,1H),7.10(d,J=7.7Hz,1H),7.01(dd,J=15.2,4.6Hz,1H),,6.57(dd,J=15.2,1.8Hz,1 H),5.85(td,J=57.2,3.1Hz,1H),4.19-4.10(m,1H),2.96(s,3H),2.48-2.43(m,1H),1.97-1.87( m,1H),1.45-1.40(m,1H),1.32(m,1H),1.10-1.02(m,1H),0.75-0.63(m,2H),0.53-0.39(m,2H).

[0738] Example 37 N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-phenoxythiazole-5-carboxamide

[0739] Compound 37 was synthesized according to Example 16, by replacing phenol with 2-fluoro-3-hydroxypyridine to obtain compound 37.

[0740] MS(ESI) m / z 469.1 [M+H] +

[0741] 1H NMR (400MHz, CDCl3) δ7.48-7.37(m,2H),7.25-7.21(m,1H),7.18-7.08(m,3H),6.97(dd, J=15.1,4.6Hz,1H),6.49(dd,J=15.1,1.7Hz,1H),5.84(td,J=57.2,3.2Hz,1H),4.18-4. 09(m,1H),2.91(s,3H),2.48-2.43(m,1H),2.05-1.88(m,1H),1.42-1.37(m,1H),1.35-1 .28(m,1H),1.04-0.93(m,1H),0.72-0.65(m,1H),0.63-0.54(m,1H),0.48-0.36(m,2H).

[0742] Example 38 N-(S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-2-((1R,2R)-2-(difluoromethyl)cyclopropyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide

[0743] The synthesis of compound 38 is described in Example 36, where compound 36a was replaced with compound 38a to obtain compound 38.

[0744] MS(ESI) m / z 488.0 [M+H] +

[0745] 1 H NMR (400MHz, CDCl3) δ8.46-8.09(m,2H),8.02-7.97(m,1H),7.46-7.43(m,1H),6.89-6.78(m,2H),6.07-5.78(m,1H),4.06 -4.01(m,1H),3.01(s,3H),2.75-2.67(m,1H),1.93-1.90(m,1H),1.41-1.37(m,1H),1.23-1.19(m,2H),0.55-0.34(m,4H).

[0746] Example 39 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)enyl)-2-(N-methylethylamino)-4-phenoxythiazole-5-carboxamide

[0747] Step 1: ethyl 2-(N-methylethylamino)thiazole-5-carboxylate 39b

[0748] Compound 39a (3.0 g, 15.66 mmol) was dissolved in 1,4-dioxane (30 mL), and N-methylethylamine (2.23 g, 31.31 mmol) and DIEA (6.07 g, 46.97 mmol) were added. The mixture was reacted at 90 °C for 3 h. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 39b (3.0 g).

[0749] MS(ESI) m / z 215.1 [M+H] +

[0750] Step 2: Ethyl 2-(N-methylethylamino)-4-iodothiazole-5-carboxylate 39c

[0751] Compound 39b (3.4 g, 15.87 mmol) was dissolved in THF (40 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (17.45 mL, 1.0 M, 17.45 mmol) was added dropwise at -78°C, and the reaction was carried out under nitrogen protection for 1 h. I₂ (8.86 g, 34.91 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture. The reaction was carried out at room temperature for 18 h. After the reaction was complete, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride to the reaction mixture under ice bath conditions. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound 39c (2.6 g).

[0752] MS(ESI) m / z 340.9 [M+H] +

[0753] Step 3: Ethyl 2-(N-methylethylamino)-4-phenoxythiazole-5-carboxylate 39d

[0754] Compound 39c (1.0 g, 2.94 mmol) was dissolved in DMF (10 mL), and phenol (555 mg, 5.88 mmol), 1,10-phenanthroline (106 mg, 0.588 mmol), cuprous iodide (112 mg, 0.588 mmol), and cesium carbonate (1.92 g, 5.88 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 110 °C for 18 h. The reaction solution was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 39d (800 mg).

[0755] MS(ESI) m / z 307.0 [M+H] +

[0756] Step 4: Lithium 2-(N-methylethylamino)-4-phenoxythiazole-5-carboxylate 39e

[0757] Compound 39d (200 mg, 0.65 mmol) was dissolved in methanol (5.0 mL) and water (1.0 mL), and lithium hydroxide (78 mg, 3.26 mmol) was added. The mixture was reacted at 40 °C for 18 h. After the reaction was complete, the crude product, yellow compound 39e (200 mg), was concentrated under reduced pressure and used directly in the next step.

[0758] MS(ESI) m / z 279.0 [M+H] +

[0759] Step 5 (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)enyl)-2-(N-methylethylamino)-4-phenoxythiazole-5-carboxamide 39

[0760] Compound 39e (200 mg, crude) was dissolved in DMF (2 mL), and 7 g (236 mg, 0.72 mmol), DIEA (278 mg, 2.16 mmol), and HATU (546 mg, 1.44 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC to obtain compound 39 (19.8 mg), a white solid.

[0761] MS(ESI) m / z 436.1 [M+H] +

[0762] 1 H NMR (400MHz, CDCl3) δ7.42-7.35(m,2H),7.23-7.14(m,3H),6.98(dd,J=15.2 ,4.4Hz,1H),6.88(d,J=7.6Hz,1H),6.46(dd,J=15.2,1.8Hz,1H),4.19-4.10( m,1H),3.42(q,J=7.1Hz,2H),2.99(s,3H),2.90(s,3H),1.17(t,J=7.1Hz,3H) ,0.99-0.90(m,1H),0.68-0.60(m,1H),0.58-0.50(m,1H),0.46-0.34(m,2H).

[0763] Example 40 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-ethynylcyclopropyl)-4-phenoxythiazol-5-carboxamide KTH052058

[0764] Step 1: Methyl 2-(1-ethynylcyclopropyl)-4-phenoxythiazole-5-carboxylate 40a

[0765] Compound 20i (10.0 mg, 0.03 mmol) was dissolved in methanol, and potassium carbonate (7.26 mg, 0.04 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (13 mg, 0.09 mmol) were added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to give colorless liquid 40a (10.0 mg).

[0766] MS(ESI) m / z 300.1 [M+H] +

[0767] Step 2: 2-(1-ethynylcyclopropyl)-4-phenoxythiazole-5-carboxylic acid 40b

[0768] Compound 40a (8.0 mg, 0.027 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), and lithium hydroxide (1.92 mg, 0.080 mmol) was added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the solution was concentrated under reduced pressure to give a white solid 40b (9.0 mg, crude), which was used directly for the next step.

[0769] MS(ESI) m / z 286.0 [M+H] +

[0770] Step 3 (S,E)-N-(1-Cyclopropyl-3-(Methanesulfonyl)allyl)-2-(1-Ethynylcyclopropyl)-4-phenoxythiazol-5-carboxamide 40

[0771] Compound 40b (9.0 mg, crude) was dissolved in DMF (1 mL), and 7 g of compound 40b (15.6 mg, 0.047 mmol), DIEA (12.2 mg, 0.095 mmol), and HATU (18.0 mg, 0.047 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered, and compound 40 (2.3 mg) was obtained as a white solid by HPLC.

[0772] MS(ESI) m / z 443.1 [M+H] +

[0773] 1H NMR (400MHz, CDCl3) δ7.43-7.35(m,2H),7.21(t,J=7.4Hz,1H),7.14-7.06(m,3H),6.97(dd,J=15.2,4.6Hz,1H),6.46(dd,J=15.1,1.7Hz,1H),4.20-4. 09(m,1H),2.91(s,3H),2.31(s,1H),1.67-1.60(m,2H),1.58-1.56(m,2H), 1.02-0.92(m,1H),0.71-0.62(m,1H),0.60-0.52(m,1H),0.48-0.35(m,2H).

[0774] Example 41 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-(methoxymethyl)cyclopropyl)-4-phenoxythiazole-5-carboxamide

[0775] Step 1: ethyl 2-(1-(hydroxymethyl)cyclopropyl)thiazole-5-carboxylate 41a

[0776] Compound 20e (12.7 g, 34.36 mmol) was dissolved in ethanol (130 mL), and magnesium sulfate (8.27 g, 68.72 mmol) and methylmalonyl chloride (5.12 g, 34.02 mmol) were added. The mixture was reacted at 80 °C for 18 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 41a (1.0 g).

[0777] MS(ESI) m / z 228.0 [M+H] +

[0778] Step 2: Ethyl 2-(1-(methoxymethyl)cyclopropyl)thiazole-5-carboxylate 41b

[0779] Compound 41a (300 mg, 1.32 mmol) was dissolved in DMF (3.0 mL), cooled to 0 °C, and sodium hydride (158.4 mg, 3.96 mmol, 60% purity) was added. After stirring for 30 minutes, iodomethane (562 mg, 3.96 mmol) was added, and the mixture was slowly heated to room temperature for 2.5 h. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 41b (170 mg).

[0780] MS(ESI) m / z 242.0 [M+H] +

[0781] Step 3: Ethyl 4-iodo-2-(1-(methoxymethyl)cyclopropyl)thiazole-5-carboxylate 41c

[0782] Compound 41b (150 mg, 0.62 mmol) was dissolved in THF (3 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (1.86 mL, 1.0 M, 1.86 mmol) was added dropwise at -78 °C, and the reaction was carried out under nitrogen protection for 1 h. I₂ (473 mg, 1.86 mmol) was then dissolved in tetrahydrofuran and added dropwise to the reaction mixture, which was then heated to room temperature and reacted for 18 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice bath conditions, followed by extraction with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain compound 41c (40 mg).

[0783] MS(ESI) m / z 368.0 [M+H] +

[0784] Step 4: 2-(1-(methoxymethyl)cyclopropyl)-4-phenoxythiazole-5-carboxylic acid ethyl ester 41d

[0785] Compound 41c (40.0 mg, 0.11 mmol) was dissolved in DMF (1 mL), and phenol (30.8 mg, 0.33 mmol), 1,10-phenanthroline (3.93 mg, 0.021 mmol), cuprous iodide (4.15 mg, 0.021 mmol), and cesium carbonate (106.0 mg, 0.33 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 90 °C for 18 h. The reaction solution was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 41d (20.0 mg).

[0786] MS(ESI) m / z 334.1 [M+H] +

[0787] Step 5: 2-(1-(methoxymethyl)cyclopropyl)-4-phenoxythiazol-5-carboxylic acid 41e

[0788] Compound 41d (20.0 mg, 0.06 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), and lithium hydroxide (7.18 mg, 0.30 mmol) was added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 41e (20.0 mg), which was used directly in the next step.

[0789] MS(ESI) m / z 306.1 [M+H] +

[0790] Step 6 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1-(methoxymethyl)cyclopropyl)-4-phenoxythiazole-5-carboxamide 41

[0791] Compound 41e (20.0 mg, crude) was dissolved in DMF (1 mL), and 7 g of compound 41e (32.37 mg, 0.098 mmol), DIEA (25.40 mg, 0.20 mmol), and HATU (37.36 mg, 0.098 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered, and compound 41 (8.8 mg) was obtained as a white solid by HPLC.

[0792] MS(ESI) m / z 463.1 [M+H] +

[0793] 1 H NMR (400MHz, CDCl3) δ7.42-7.35 (m, 2H), 7.21 (t, J = 7.4Hz, 1H), 7.17 -7.09(m,3H),6.97(dd,J=15.1,4.6Hz,1H),6.46(dd,J=15.1,1.8Hz,1H),4.20-4.08(m,1H),3.60(s,2H),3.41(s,3H),2.9 0(s,3H),1.34-1.28(m,2H),1.09-1.06(m,2H),1.03-0.93(m,1H),0.69-0.64(m,1H),0.60-0.54(m,1H),0.45-0.37(m,2H).

[0794] Example 42 (S,E)-2-(2-cyanopropyl-2-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazol-5-carboxamide

[0795] Step 1: 2-(4-chlorothiazol-2-yl)-2-cyanoacetic acid tert-butyl ester 42b

[0796] Compound 9a (10.0 g, 65 mmol) was dissolved in DMF (100 mL), and cesium carbonate (42.35 g, 130 mmol) and tert-butyl cyanoacetate (13.73 g, 97.4 mmol) were added. The mixture was reacted at 80 °C for 3 h. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 42b (18 g), a yellow liquid.

[0797] MS(ESI) m / z 259.1 [M+H] +

[0798] Step 2: 2-(4-chlorothiazo-2-yl)acetonitrile 42c

[0799] Compound 42b (15 g, 58.1 mmol) was dissolved in dry DCM (150 mL), and trifluoroacetic acid (75 mL) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to the crude product. The crude product was purified by silica gel column chromatography to give compound 42c (2 g), a yellow liquid.

[0800] MS(ESI) m / z 158.9 [M+H] +

[0801] Step 3: 2-(4-chlorothiazo-2-yl)-2-methylpropionitrile 42d

[0802] Compound 42c (460 mg, 2.91 mmol) was dissolved in DMF (5 mL). Sodium hydride (353 mg, 8.8 mmol, 60% purity) was added at 0 °C, and the reaction was allowed to proceed for 0.5 hours. Then, iodomethane (1.2 g, 8.45 mmol) was added, and the reaction was continued for another 0.5 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 42d (520 mg), a colorless liquid.

[0803] MS(ESI) m / z 187.0 [M+H] +

[0804] Step 4: Ethyl 4-chloro-2-(2-cyanopropyl-2-yl)thiazolyl-5-carboxylate 42e

[0805] Compound 42d (520 mg, 2.8 mmol) was dissolved in THF (10 mL), and a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex (4.2 mL, 1.0 M, 4.2 mmol) was added dropwise at -78 °C under nitrogen for 1 h. Diethyl pyrocarbonate (679 mg, 4.2 mmol) was dissolved in THF and added dropwise to the reaction mixture. The mixture was heated to 0 °C until the reactants were completely reacted. At 0 °C, saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 1) to give compound 42e (310 mg), a pale yellow solid.

[0806] MS(ESI) m / z 259.0 [M+H] +

[0807] Step 5: 2-(2-cyanopropyl-2-yl)-4-phenoxythiazol-5-carboxylic acid ethyl ester 42f

[0808] Compound 42e (100 mg, 0.388 mmol) was dissolved in DMF (2 mL), and phenol (73 mg, 0.78 mmol) and cesium carbonate (189.4 mg, 0.58 mmol) were added. The mixture was reacted at 100 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1) to give compound 42f (130 mg), a colorless oil.

[0809] MS(ESI) m / z 317.0 [M+H] +

[0810] Step 6: 42g of 2-(2-cyanopropyl-2-yl)-4-phenoxythiazol-5-carboxylic acid

[0811] Compound 42f (130 mg, 0.41 mmol) was dissolved in ethanol (1 mL), and a solution of sodium hydroxide (46.5 mg, 1.16 mmol) in water (0.5 mL) was added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, water (10 mL) was added, the pH was adjusted to 3 with phosphoric acid, and the mixture was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 42 g (90 mg) as a yellow solid.

[0812] MS(ESI) m / z 289.0 [M+H] +

[0813] Step 7 (S,E)-2-(2-cyanopropyl-2-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxythiazol-5-carboxamide 42

[0814] Compound 42 g (90 mg, 0.31 mmol) was dissolved in DMF (2 mL), and 7 g (130 mg, 0.375 mmol), DIEA (202 mg, 1.566 mmol), and HATU (178 mg, 0.468 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered, and compound 42 (52 mg) was obtained as a white solid by HPLC.

[0815] MS(ESI) m / z 446.2 [M+H] +

[0816] 1H NMR (400MHz, DMSO) δ8.19(d,J=8.3Hz,1H),7.42(q,J=8.9Hz,2H),7.22(t,J=7.6Hz,3H),6.82(dt,J=27.3,10.4Hz,2H),4.02(dd,J=13.5,8. 2Hz,1H),2.98(s,3H),1.75(s,6H),1.21–1.15(m,1H),0.53(dd,J=10.6,6.7Hz,1H),0.41(ddd,J=14.7,8.7,4.4Hz,2H),0.31–0.22(m,1H).

[0817] Example 43 (S,E)-2-(2-cyanopropyl-2-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoropyridin-3-yl)oxy)thiazolyl-5-carboxamide

[0818] The synthesis of compound 43 is based on compound 42, but with phenol replaced by 2-fluoro-3-hydroxypyridine.

[0819] MS(ESI) m / z 465.2 [M+H] +

[0820] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.4Hz,1H),8.12(d,J=4.7Hz,1H),8.02(t,J=8.9Hz,1H),7.47(dd,J=7.9,4.9Hz,1H),6.93–6.77(m,2H),4.06 (td,J=8.8,4.1Hz,1H),3.02(s,3H),1.72(s,6H),1.22–1.15(m,1H),0.6 2–0.53(m,1H),0.52-0.46(m,1H),0.45-0.39(m,1H),0.37-0.31(m,1H).

[0821] Example 44 2-(2-cyanocyclopropyl)-N-((S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-4-phenoxythiazole-5-carboxamide

[0822] The synthesis of compound 44 is based on compound 42, with intermediate 44b replacing compound 42e.

[0823] MS(ESI) m / z 444.2 [M+H] +

[0824] 1 H NMR (400MHz, CDCl3) δ7.45-7.38(m,2H),7.25-7.17(m,4H),7.03-6.94(m,1H),6.57-6.47(m,1H),4.18-4.10(m,1H),2.94(s,1.5H),2.92(s, 1.5H),2.77-2.68(m,1H),2.05-1.96(m,1H),1.94-1.86(m,1H),1.66- 1.62(m,1H),1.07-0.94(m,1H),0.75-0.55(m,2H),0.51-0.37(m,2H).

[0825] Example 45N-(S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoropyridin-3-yl)oxy)-2-((R)-3-fluorotetrahydrofuran-3-yl)thiazolyl-5-carboxamide (45-P1 or 45-P2)

[0826] N-(S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoropyridin-3-yl)oxy)-2-((S)-3-fluorotetrahydrofuran-3-yl)thiazolyl-5-carboxamide (45-P1 or 45-P2)

[0827] The synthesis of compounds 45-P1 and 45-P2 is based on compound 43, with compound 45a replacing compound 42e, and compounds 45-P1 and 45-P2 were obtained by SFC separation.

[0828] Chiral preparation conditions: IC, 10μm, 30*250mm, Mobile phase A: CO2, Mobile phase B: MeOH, Detection wavelength: 214nm / 254nm, Flow rate: 80mL / min, Column temperature: Room temperature, Isocratic elution program: Mobile phase A: Mobile phase B = 80:20 (V / V)

[0829] Chiral analysis conditions: IA, 5μm, 4.6mm*250mm, mobile phase A: CO2, mobile phase B: MEOH, detection wavelength: 214nm, flow rate: 3.0mL / min, column temperature: 35℃, isocratic elution program: mobile phase A: mobile phase B = 85:15 (V / V)

[0830] Compound 45-P1: MS (ESI) m / z 486.2 [M+H] + SFC retention time: 19.77 min

[0831] 1H NMR(400MHz, CDCl3)δ8.11(dt,J=4.9,1.6Hz,1H),7.95-7.88(m,1H),7.30(dd,J =7.9,4.8Hz,1H),7.16(d,J=7.6Hz,1H),7.00(dd,J=15.1,4.7Hz,1H),6.58(dd, J=15.1,1.7Hz,1H),4.23-4.06(m,4H),4.00(dd,J=33.3,10.8Hz,1H),2.96(s,3 H),2.57-2.42(m,2H),1.12-1.01(m,1H),0.78-0.62(m,2H),0.54-0.40(m,2H).

[0832] 19 F NMR(376MHz, CDCl3)δ-81.34(s),-143.82(s).

[0833] Compound 45-P2: MS (ESI) m / z 486.2 [M+H] + SFC retention time: 15.02 min

[0834] 1 H NMR (400MHz, CDCl3) δ8.12(dt,J=4.9,1.6Hz,1H),7.95-7.88(m,1H),7.31(dd,J=8.0,4.8Hz,1H),7.16(d,J=7.6Hz,1H),7.00(dd,J=15.2,4.7Hz ,1H),6.58(dd,J=15.2,1.7Hz,1H),4.24-3.94(m,5H),2.96(s,3H),2.5 6-2.40(m,2H),1.12-1.00(m,1H),0.79-0.61(m,2H),0.54-0.41(m,2H).

[0835] 19 F NMR(376MHz, CDCl3)δ-81.35(s),-143.81(s).

[0836] Example 46N-((1S,E)-1-cyclopropyl-3-(S-methylsulfonylimino)allyl)-2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxamide

[0837] Compound 46a (60 mg, crude, 0.18 mmol) and compound 12b (71 mg, 0.24 mmol) were dissolved in DMF (2 mL). DIEA (186 mg, 1.44 mmol) and T3P (183 mg, 50%, 0.29 mmol) were added, and the reaction was continued at room temperature for 24 h. The reaction was quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative silica gel plate chromatography (DCM / MeOH = 10 / 1) to obtain compound 46 (15 mg), a white solid.

[0838] MS(ESI) m / z 461.2 [M+H] +

[0839] 1 H NMR (400MHz, CDCl3) δ8.14-8.10(m,1H),8.03-7.96(m,1H),7.34-7.29(m,1H),7.23(m,1H),6.97-6.90(m,1H),6.72-6.6 5(m,1H),4.22-4.13(m,1H),3.03(s,3H),2.22(t,J=7.6Hz,3H),1.11-1.03(m,1H),0.76-0.65(m,2H),0.54-0.42(m,2H).

[0840] Example 47 N-((1R,E)-1-cyclopropyl-3-(S-methylsulfonylimino)allyl)-2-(1,1-difluoroethyl)-4-phenoxythiazole-5-carboxamide

[0841] The synthesis of compound 47 is described in Example 46, with compound 47a replacing compound 46a.

[0842] MS(ESI) m / z 461.2 [M+H] +

[0843] 1 H NMR (400MHz, CDCl3) δ8.14-8.10(m,1H),8.03-7.96(m,1H),7.34-7.29(m,1H),7.23(m,1H),6.97-6.90(m,1H),6.72-6.6 5(m,1H),4.22-4.13(m,1H),3.03(s,3H),2.22(t,J=7.6Hz,3H),1.11-1.03(m,1H),0.76-0.65(m,2H),0.54-0.42(m,2H).

[0844] Example 48 (S,E)-N-(1-cyclopropyl-3-(methanesulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)thiazole-5-carboxamide

[0845] The synthesis of compound 48 is based on Example 27, with 2-chloro-3-hydroxypyridine replaced by 1-methyl-4-hydroxy-1H-pyrazole.

[0846] MS(ESI)m / z 447.2[M+H]+

[0847] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=14.3Hz,2H),7.21(d,J=7.5Hz,1H),7.03(dd,J=15.2,4.7Hz,1H),6.58-6.62(m,1H),4.18 -4.23(m,1H),3.95(s,3H),2.99(s,3H),2.05(t,J=18.3Hz,3H),1.01-1.17(m,1H),0.66-0.84(m,2H),0.42-0.59(m,2H).

[0848] Example 49 N-((S,E)-1-cyclopropyl-3-(methanesulfonyl)allyl)-4-((2-fluoropyridin-3-yl)oxo)-2-(3-methyltetrahydrofuran-3-yl)thiazolyl-5-carboxamide

[0849] The synthesis of compound 49 is described in Example 43, with compound 49a replacing compound 42e.

[0850] MS(ESI) m / z 482.2 [M+H] +

[0851] 1H NMR (400MHz, CDCl3) δ8.10-8.06(m,1H),8.02-7.95(m,1H),7.31-7.26(m,1H),7.20- 7.15(m,1H),7.00(dd,J=15.2,4.6Hz,1H),6.57(dd,J=15.2,1.7Hz,1H),4.20-4.11( m,1H),4.02-3.93(m,3H),3.67(d,J=8.6Hz,1H),2.95(s,3H),2.42-2.33(m,1H),2.0 5-1.96(m,1H),1.50(s,3H),1.11-1.00(m,1H),0.76-0.62(m,2H),0.52-0.40(m,2H).

[0852] The synthesis of control compound 1 is described in Example 87 of patent WO2024010782.

[0853] Test Example 1: Test of the compound's activity against WRN(517-1238) enzyme

[0854] This experiment investigated the inhibitory effect of the compound on the activity of WRN(517-1238) enzyme by examining its effect on the activity of WRN(517-1238) enzyme in vitro.

[0855] Experimental reagents and consumables

[0856] The compound was serially diluted using DMSO in a 384PP Plate compound dilution plate. 0.15 μL of the compound was transferred to a 384 reaction microplate (Corning 4514) using an Echo, ensuring a final DMSO concentration of 1% (double replicate). 5 μL of WRN (517-1238) enzyme solution was added to each well of the 384 reaction microplate and incubated at 25°C for 10 minutes. Wells containing 1% DMSO and enzyme served as the high control, and wells containing the same concentration of DMSO and buffer served as the low control. 5 μL of dsDNA solution and 5 μL of ATP solution were added to each well and incubated at 25°C for 20 minutes (final concentration: 1 nM WRN, 5 nM dsDNA, 50 μM ATP). Fluorescence signal values ​​were read on a BMG (CLARIO Star Plusacu) microplate reader (Ex: 620 nm, Em: 685 nm). The percentage of inhibition of the compound-treated pores is normalized between high control and low control: %inhibition = ((signal value - high control value)) / (signal value - high control value) 化合物处理 () / (signal value high control - signal value low control)*100). Then, fit the four-parameter IC using XLfit 5.5.0. 50 The curve was analyzed.

[0857] Test Example 2: Test of the inhibitory activity of the compound on the proliferation of SW48 tumor cells

[0858] Prepare complete culture medium (L-15 + 10% FBS + 1% P / S) to revive SW48 cells (ATCC), passage them two times, centrifuge to collect and count the cells in the logarithmic growth phase, resuspend the cells to an appropriate concentration, and seed the cell suspension into 96-well plates, adding 100 μL of cell suspension to each well, with a seeding density of 5000 cells / well. Place the 96-well plates in a CO2 incubator (0% CO2) overnight, then aspirate 50 μL of the supernatant culture medium and add 40 μL of fresh culture medium. The test compound was prepared as a stock solution using DMSO. Nine concentration gradients were obtained by stepwise 4-fold dilution with DMSO, starting at a maximum concentration of 2.5 mM. The test compound was diluted 25-fold with culture medium. 10 μL of each solution was added to a 96-well cell plate containing 90 μL of cells. Cell-free culture medium (containing 0.4% DMSO) was added to the Min control wells, and 10 μL of a DMSO-cell culture medium mixture (final DMSO concentration 0.4%) was added to the Max control wells. The plates were incubated at 37°C, 0% relative humidity (≥90%) for 120 h. 50 μL / well CellTiter Glo was added to terminate the reaction. The plates were incubated at room temperature in the dark for 10 min, gently shaken, and then detected using Envision. The fluorescence value (RLU) of each well was read, and the cell inhibition rate (%) was calculated using the formula: Cell Growth Inhibition Rate (%) = (1 - As / Ac) × 100. Where As: RLU sample (cells + CTG + test compound) - RLU Min (cell-free culture medium), Ac: RLU normal growth cell control (cells + CTG + DMSO) - RLU Min (cell-free culture medium). Enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in Excel, and use Graphpad Prism 8 software to fit the formula Y = Bottom + (Top - Bottom) / (1 + (IC)) using the built-in four-parameter fitting formula. 50 The half-maximal inhibitory concentration (IC50) of each compound was calculated using the formula ( / X)*HillSlope). 50 value.

[0859] Table 2. Results of the test compounds on the inhibition of SW48 tumor cell proliferation

[0860] IC 50( nM): 0<A≤50; 50<B≤200; 200<C≤1000; 1000 <D

[0861] Experimental results show that the compound of this invention has a good inhibitory effect on the proliferation of SW48 tumor cells.

[0862] Test Example 3: Mouse Pharmacokinetics Test

[0863] Six male ICR mice were used, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. The solvent used in the experiment was 10% NMP + 15% Kolliphor EL + 1% Sloutol + 74% (20% HP-β-CD). Intravenous administration was 5 mL / kg at a concentration of 0.2 mg / mL; oral administration was 10 mL / kg at a concentration of 1 mg / mL. Overnight fasted mice were used. The test compound was dissolved in the solvent and administered intravenously or by gavage to the mice. Blood samples were collected from the cheeks of mice at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration, approximately 0.05 mL per sample. The samples were anticoagulated with EDTAK2 and placed on moist ice. After collection, the blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000g, 3 minutes, 2-8℃). Plasma samples were stored at -80°C before analysis. Blood drug concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on blood drug concentration data at different time points, providing the AUC. 0-t AUC 0-∞ MRT 0-∞ C max T max 、 and T 1 / 2 Parameters such as their mean and standard deviation.

[0864] Table 3 Results of mouse pharmacokinetic studies of the tested compounds

[0865] Experimental results show that, compared with control compound 1, the compound of the present invention exhibits higher exposure and oral bioavailability, and has better pharmacokinetic properties.

[0866] Test Example 4: Beagle Dog Pharmacokinetic Study

[0867] The pharmacokinetic study in beagle dogs used female beagle dogs (9-11 kg, provided by Yizheng Anlimao Biotechnology Co., Ltd.). The test solvent was 10% NMP + 15% Kolliphor EL + 1% Sloutol + 74% (20% HP-β-CD). The test compound was prepared into a clear solution of 1 mg / mL using the solvent. The administration volumes were 1 mL / kg for intravenous administration and 5 mL / kg for gavage. Three beagle dogs that had been fasted overnight were used. The test compound was administered intravenously or by gavage. Blood samples of 1 mL were collected from the forelimb vein at 0 h (before administration) and at 0.083, 0.25, 1, 2, 4, 6, 8, and 24 h after administration. The blood was anticoagulated with EDTA-2K. The mixture was thoroughly vortexed and centrifuged at 6000 rpm for 3 minutes. Blood drug concentrations were determined by LC-MS / MS. Relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 pharmacokinetic software with a non-compartmental model linear logarithmic trapezoidal method.

[0868] Table 4. Results of the beagle dog pharmacokinetic studies of the tested compounds.

[0869] Experimental results show that, compared with control compound 1, the compound of the present invention exhibits higher exposure and oral bioavailability, and has better pharmacokinetic properties.

[0870] Test Example 5: Thermodynamic Solubility Test of Compounds

[0871] FaSSGF (pH=1.6), FaSSIF (pH=6.5), and PBS (pH=7.4) were commercially available reagents purchased from Biorelevant or other commonly used commercial companies. Approximately 2 mg of the compound per pH was accurately weighed and added to appropriate volumes of FaSSGF (pH=1.6), FaSSIF (pH=6.5), and PBS (pH=7.4) to obtain solutions with a concentration of 2 mg / mL. After sonication for 10 minutes, the solution was fixed on a shaker and incubated overnight (at least 8 hours) at room temperature. After shaking, the solution was sonicated for 10 minutes and centrifuged at 13000 rpm for 15 minutes. 0.1 mL of the supernatant was transferred to a new tube, shaken and rinsed for 5 minutes, and then discarded. Another 0.5 mL of the supernatant was transferred to a new tube, centrifuged at 13000 rpm for 15 minutes, and the supernatant (diluted with water if necessary) was analyzed using LCUV (LC-MS if UV detection is not possible). Sample concentration was quantified using a fitted standard (3–5 points).

[0872] Table 5. Results of thermodynamic solubility tests on the tested compounds.

[0873] Experimental results show that the solubility of the compound of the present invention is significantly improved compared with control compound 1.

[0874] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

A compound of formula (I), its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal form, its isotopic derivatives, its prodrugs, its metabolites, its solvates, or its hydrates. in, X is selected from O, S, Se, CR8, N, or NR9; Y is selected from O, S, CR 10 , N, or NR 11 The premise is It has aromatic properties; R8, R9, R 10 and R 11 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; R1 is selected from the following group: (1)C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, C 6-12 Aryl, C 2-6 Alkenyl, 4-6 membered heterocyclic, 5-12 heteroaryl; the above groups are optionally surrounded by 1, 2 or 3 R groups. 1a And 1, 2 or 3 R 1b Replace; R 1a Optionally by 1, 2 or 3 R 1a-1 Replace; R 1b Optionally by 1, 2 or 3 R 1b-1 replace; R 1a and R 1b Each group is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, carboxyl, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 alkylamine group, C 6-12 aryl, 5-12 heteroaryl; or R 1a R 1b Together with the atoms they are attached to, they form C 3-6 A carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered heterocycle contains 1, 2, or 3 heteroatoms selected from O, N, and S, wherein R 1a and R 1b They can be located on the same or different atoms; the above C 3-6 The carbon ring or 3-6 membered heterocycle is optionally surrounded by 1, 2 or 3 Rs 1c replace; Each R 1c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; R 1a-1 and R 1b-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 6-acetylinyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; (2)-NR 1e R 1d ; R 1e and R 1d Each of them independently selected from the following group: C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1e Optionally by 1, 2 or 3 R 1e-1 Replace; R 1d Optionally by 1, 2 or 3 R 1d-1 Replace; or R 1e R 1d Together with the N atoms they are attached to, they form 3-8 membered heterocycles, wherein the 3-8 membered heterocycles contain 1, 2, or 3 heteroatoms selected from O, N, and S; the 3-8 membered heterocycles are optionally separated by 1, 2, or 3 R atoms. 1g replace; Each R 1g Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; or two R groups 1g They can together form C 3-6 Carbon rings or 3-6 membered heterocycles, with two Rs 1g They can be located on the same or different ring atoms; R 1e-1 and R 1d-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 6-acetylinyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; (3)-S-R 1j ; R 1j Selected from the following group: C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1j Optionally by 1, 2 or 3 R 1k replace; Each R 1k Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; (4)-O-R 1m ; R 1m Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, C 2-6 alkenyl, C 3-8 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1m Optionally by 1, 2 or 3 R 1n replace; Each R 1n Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; R2 is -OR 12 or -SR 12 , where R 12 Selected from the following group: C 3-8 cycloalkyl, C 1-6 Alkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic; R 12 The land can be optionally divided by 1, 2, 3, 4, 5 or 6 Rs. 12a Replace; R 12a Choose any 0, 1, 2 or 3 Rs 12a-1 replace; Each R 12a and R 12a-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; W is: * indicates the location connected to the parent core; R3 is selected from the following groups: H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl; R3 is optionally surrounded by 1, 2 or 3 Rs 3a replace; Each R 3a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; R4 is selected from the following groups: H, D, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl; R4 optionally surrounded by 1, 2 or 3 Rs 4b replace; Each R 4b Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 1-6 alkenyl, C 1-6 Haloalkenyl, C 1-6 Alkylamine group; R 4a -C 0-4 Alkylene-R 4a-1 , where R 4a-1 Selected from the following group: C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkenyl, 5-6 membered heterocyclic, 5-6 membered aromatic heterocyclic, phenyl, 3-12 membered biheterocyclic; R 4a Optionally by 1, 2 or 3 R 4c replace; Each R 4c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 alkylamine group, C 6-10 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic; R5 is selected from H and D; R6 is selected from H, D, halogen, or cyano; R7 is selected from the following group: C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered oxocyclic, 3-8 membered nitrogen-containing heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; R7 optionally covered with 1, 2 or 3 Rs 7a replace; Each R 7a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 1-6 alkenyl, C 1-6 Haloalkenyl, C 1-6 Alkylamine group; Or, R7, R 4a Together with the atoms they are attached to, they form C 7-15 A carbon ring or a 7-15 membered heterocycle, wherein the formed 7-15 membered heterocycle contains 1-7 heteroatoms selected from O, S, or N; the formed C 7-15 The carbon ring or 7-15 membered heterocycle is optionally surrounded by 1, 2, 3, 4 or 5 R... 7b replace; Each R 7b Independently selected from the following groups: H, D, halogen, cyano, amino, hydroxyl, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-8 Cycloalkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 1-6 Alkylamine group; Each R 7c Independently selected from the following groups: H, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-8 cycloalkyl, C 1-4 Halogenated alkyl groups. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, R1 is selected from the following group: (1)C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-8 membered heterocyclic alkenyl, phenyl, naphthyl, C 2-4 alkenyl, 4-6 membered heterocyclic, 5-9 heteroaryl; the above groups are optionally surrounded by 1, 2 or 3 R groups. 1a And 1, 2 or 3 R 1b Replace; R 1a Optionally by 1, 2 or 3 R 1a-1 Replace; R 1b Optionally by 1, 2 or 3 R 1b-1 replace; R 1a and R 1b Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 alkylamine group, C 6-12 aryl, 5-9 quinone heteroaryl; or R 1a R 1b Together with the atoms they are attached to, they form C 3-6 A carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered heterocycle contains 1, 2, or 3 heteroatoms selected from O, N, and S, wherein R 1a and R 1b They can be located on the same or different atoms; the above C 3-6 The carbon ring or 3-6 membered heterocycle is optionally surrounded by 1, 2 or 3 Rs 1c replace; Each R 1c Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; R 1a-1 and R 1b-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 4-Alynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; (2)-NR 1e R 1d ; R 1e and R 1d Each of them independently selected from the following group: C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2-4 alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1e Optionally by 1, 2 or 3 R 1e-1 Replace; R 1d Optionally by 1, 2 or 3 R 1d- 1 replaces; or R 1e R 1d Together with the N atoms they are attached to, they form 3-6 membered heterocycles, wherein the 3-8 membered heterocycles contain 1, 2, or 3 heteroatoms selected from O, N, and S; the aforementioned 3-6 membered heterocycles are optionally separated by 1, 2, or 3 R atoms. 1g replace; Each R 1g Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-6 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; or two R groups 1g They can together form C 3-6 Carbon rings or 3-6 membered heterocycles, with two Rs 1g They can be located on the same or different ring atoms; R 1e-1 and R 1d-1 Each is independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C. 1-4 Alkyl, C 1- 4-Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2- 4-Alynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; (3)-S-R 1j ; R 1j Selected from the following group: C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2-4 alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1j Optionally by 1, 2 or 3 R 1k replace; Each R 1k Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; (4)-O-R 1m ; R 1m Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, naphthyl, C 2- 4-Alkenyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic, 5-6 membered heteroaryl; R 1m Optionally by 1, 2 or 3 R 1n replace; Each R 1n Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; Preferably, R1 is selected from the group consisting of: * indicates the location of the link key, which is connected to the mother core. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, R3 is selected from the following group: H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, The R 4a -C 0-2 Alkylene-R 4a-1 , where R 4a-1 Selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkenyl, 5-6 membered heterocyclic group, 5-6 membered aromatic heterocyclic group, phenyl, 6-10 membered biheterocyclic group; Preferably, the R 4a Selected from the following group: * indicates the location of the link key, which is connected to the mother core. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, The R7 is selected from the following group: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl, 3-6 membered oxoheterocyclic, 3-6 membered nitrogen-heterocyclic. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, R2 is -OR 12 , where R 12 Selected from the following group: C 3-6 cycloalkyl, C 1-4 Alkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic; R 12 The land can be optionally divided by 1, 2, 3, 4, 5 or 6 Rs. 12a replace; Each R 12a Independently selected from the following groups: H, D, halogen, amino, cyano, hydroxyl, C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 alkynyl group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 1-4 Alkylamine group; Preferably, R2 is selected from the group consisting of: * indicates connection to the parent nucleus. The compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate as claimed in claim 1, is characterized in that, The compound has the structure shown in formula (I-1), (I-2), or (I-3): The definitions of R1, R2, R9, and W are as described in claim 1. The compound of claim 1, its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates, or its hydrates, is characterized in that, The compounds are selected from the following group: A pharmaceutical composition comprising the compound of any one of claims 1-8, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotopic derivative, its prodrug, its metabolite, its solvate, or its hydrate; and a pharmaceutically acceptable carrier. Use of a compound, stereoisomer, optical isomer, pharmaceutically acceptable salt, crystal form, isotope derivative, prodrug, metabolite, solvate or hydrate thereof, or pharmaceutical composition as described in claim 9 in the preparation of a medicament for treating WRN helicase-mediated diseases. Preferably, the disease is a tumor; more preferably, the disease is a microsatellite instability tumor; even more preferably, the tumor is a tumor characterized by high microsatellite instability (MSI-H) or having defective mismatch repair (dMMR) or "dMMR features"; in, The microsatellite unstable tumors include, but are not limited to, uterine fibroids, endometrial cancer, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cyst carcinoma. Tumors with "defective mismatch repair" (dMMR) or "dMMR features" include, but are not limited to, lung cancer, breast cancer, kidney cancer, colorectal cancer, ovarian cancer, prostate cancer, upper respiratory and digestive tract cancer, gastric cancer, endometrial cancer, liver cancer, pancreatic cancer, hematopoietic and lymphatic tissue cancer, skin cancer, thyroid cancer, pleural cancer, autonomic nervous system tumors, soft tissue tumors, rhabdomyosarcoma, melanoma, and other tumors.

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