DERIVADO DE AMIDA AROMÁTICA E MÉTODO DE PREPARAÇÃO PARA O MESMO E USO DO MESMO

Abstract

The present invention relates to an aromatic amide derivative, a preparation method therefor, and the use of a pharmaceutical composition containing the derivative in medicine. Specifically, the present invention relates to an aromatic amide derivative as represented by general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and the use thereof as a therapeutic agent, in particular a KIF18A inhibitor, wherein the definition of each substituent in general formula (I) is the same as the definition in the description.

Description

1 / 79 Aromatic amide derivative and method of preparation thereof and use thereof. TECHNICAL FIELD

[0001] The present invention relates to an aromatic amide derivative, a method of preparation thereof, a pharmaceutical composition containing the derivative and use thereof as a therapeutic agent, particularly as a KIF18A inhibitor. BACKGROUND

[0002] The kinesin molecule is a motor protein with a microtubule as its orbit and plays an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis, and other processes. Multiple microtubule-associated proteins (MAPs) of the kinesin-8 family play a role in regulating microtubule dynamic instability by influencing microtubule polymerization and depolymerization. KIF18A is a member of the kinesin-8 family, can move towards a positive pole with the microtubule as its orbit, and tends to bind to longer microtubules. Its activity is length-dependent and affects spindle body length, which can ensure the timed and smooth completion of sister chromosome arrangement. KIF18A has very similar functions in different species, thus being conservative.

[0003] KIF18A is a molecular motor protein that moves toward a positive pole end of a microtubule with the microtubule as an orbit, regulates chromosome congress by influencing microtubule end dynamic instability, and plays a role in a phase of mitosis. In anaphase of mitosis, this protein is ubiquitinated and degraded, which ensures precise chromosome separation during mitosis and promotes the smooth completion of mitosis and cytokinesis. In prophase of mitosis, the location of KIF18A at a positive pole end of a microtubule near a kinetochore is a necessary condition for it to perform its function. Petition 870250081292, dated 10 / 09 / 2025, page 15 / 258 2 / 79 The location of KIF18A depends not only on the motor activity of its N-terminal, but also on a caudal structural domain with microtubule-binding capacity. KIF18A is also modified by reversible protein phosphorylation / dephosphorylation, but there is still a lack of systematic study on how post-translational modification of this protein regulates KIF18A function. An estrogen receptor ERa can bind to KIF18A and promote its transcription, but it is still unclear whether KIF18A is regulated by other transcription factors, so a mechanism of KIF18A gene transcription regulation needs to be further studied. In meiosis, cells lacking KIF18A will be unable to complete meiosis, leading to dyszoospermia and testicular dysgenesis in male animals.

[0004] Studies show that the KIF18A protein is highly expressed in many cancers, including, but not limited to, hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, and similar cancers, indicating that KIF18A is closely related to the occurrence and development of tumors and may become a target for molecular diagnosis and treatment of various tumors. KIF18A expression is associated with the development of clinical colorectal cancer.Studies show that KIF18A can induce Akt phosphorylation, which silences KIF18A in mice and can obviously promote cell apoptosis. It is also hypothesized that KIF18A may promote the occurrence and development of colorectal cancer by activating a PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is related to breast tumor classification, migration, and prognosis. Studies on breast cancer show that KIF18A overexpression can lead to the generation of multinucleated cells, while low KIF18A expression can significantly weaken the tumor. Petition 870250081292, dated 10 / 09 / 2025, page 16 / 258 3 / 79 a capacity for cell proliferation in vitro and in vivo, which is due to cell apoptosis induced by microtubule-end stabilization via KIF18A and inactivation of the PI3K-Akt signal transduction pathway. Furthermore, KIF18A is upregulated at the transcription and translation levels in lung adenocarcinoma, and abnormal KIF18A expression is related to a degree of clinicopathological malignancy. KIF18 gene mutation can be observed in lung adenocarcinoma; its expression is also regulated by DNA copy number, and KIF18A gene silencing can inhibit lung adenocarcinoma cell proliferation in vivo and in vitro, thus inducing cell apoptosis and G2 / M phase blockade. Genes highly expressed in conjunction with KIF18A are all concentrated in a single cell cycle signaling pathway, so it is of great clinical significance to further study a mechanism of action of KIF18A in tumors.

[0005] There are no new drugs on the market for inhibitors targeting KIF18A, and at present, only AMG-650 from Amgen Company of the United States has entered a phase I clinical trial. As a relatively advanced research direction, there is still immense scope for exploration in correlational studies on a KIF18A target, so it is highly necessary to continuously study its mechanism of action and develop new inhibitors. SUMMARY

[0006] In view of the above technical problems, the present invention provides an aromatic amide derivative as shown by general formula (I), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof: Petition 870250081292, dated 10 / 09 / 2025, page 17 / 258 4 / 79 G (I) where: Ring A is selected from a 5-7 membered heterocycline or a 5-7 membered heteroaryl group; G is selected from or ^ ; Xi and X2 are each independently selected from CRa or an N atom; Yi, Y2, and Y3 are each independently selected from CR or an N atom, and at most two of Yi, Y2, and Y3 are N atoms at the same time; Rae R6são, each independently selected from a hydrogen, halogen, hydroxyl, cyano, alkyl or alkoxy atom, wherein the alkyl or alkoxy is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; RA is the same or different, and is each independently selected from a hydrogen, halogen, hydroxyl, cyano, alkyl or alkoxy atom, wherein the alkyl or alkoxy is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; Or, two RAs form a C(O) together with the same carbon atom to which the two RAs are attached; Li is selected from a C1-C6 alkylene bond, in which the Petition 870250081292, dated 10 / 09 / 2025, page 18 / 258 5 / 79 alkylene is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy, and one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O)r, C(O) or NRc; Rcé selected from a hydrogen or alkyl atom; L2 is selected from der3our3; R3 is each independently selected from a hydrogen or alkyl atom, wherein the alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; and R3 is preferably a hydrogen atom; R1 is selected from a hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl or heteroaryl atom, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10; R4 is selected from cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -C(O)R5, -C(O)OR5, NHC(O)R5, -NHC(O)OR5, -NR6R7, -C(O)NR6R7, -CH2NHC(O)OR5, -CH2NR6R7 or -S(O)rR5, wherein alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, SO2NR9R10or -NR9C(O)R10; R5 is each independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the Petition 870250081292, dated 10 / 09 / 2025, p. 19 / 258 6 / 79 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10; R6e R7 are each independently selected from a hydrogen, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl atom, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10; or, R6 and R7 form a 4-8 membered heterocycline together with the atoms to which R6 and R7 are attached, wherein the 4-8 membered heterocycline contains one or more N, O or S(O)r, and the 4-8 membered heterocycline is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycline, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10; R8, R9 and R10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate group. n is 0, 1, 2, 3, or 4; er is, each independently, 0, 1, or 2.

[0007] A preferred solution of the present invention provides a compound as shown by general formula (I), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, which is Petition 870250081292, dated 10 / 09 / 2025, page 20 / 258 7 / 79 a compound as shown by formula (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: (ii) (iii) the ring definitions A, Xi, X2, RA, R1, R4, Li and en are as described in the general formula (I). A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: Li is selected from a C1-C6 alkylene linkage, wherein the alkylene is optionally further replaced by one or more hydroxyl groups, and one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O)r, C(O) or NRc; r is 2; and Rcé is selected from a hydrogen or methyl atom.

[0008] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein Li is selected from a linkage, -NHSO2CH2CH2-, SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, Petition 870250081292, dated 10 / 09 / 2025, p. 21 / 258 8 / 79 NHCH2CH2- or -CH2SO2CH2CH2-.

[0009] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R1 is selected from a hydrogen, hydroxyl, alkyl, heterocyclyl, cycloalkyl or heteroaryl atom, wherein the alkyl, heterocyclyl, cycloalkyl or heteroaryl is optionally further replaced by one or more substituents selected from hydroxyl or alkyl.

[0010] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein * is h0 or h0.

[0011] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt of R1 è -S -4-KR'' same, where 5 is nυ.

[0012] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein Xi and X2 are each independently selected from CH.

[0013] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: Petition 870250081292, dated 10 / 09 / 2025, page 22 / 258 9 / 79

[0014] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from hn or n-nh

[0015] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: RA is each one independently selected from a hydrogen or methyl atom; Or, two RAs form a C(O) together with the same carbon atom. Petition 870250081292, dated 10 / 09 / 2025, page 23 / 258 10 / 79 to which the two RAs are fixed.

[0016] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R4 is each independently selected from 3-10 membered heterocyclyl or C3-C10 cycloalkyl, wherein the heterocyclyl or cycloalkyl is optionally further substituted by one or more hydroxyl or halogen groups.

[0017] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R4 is each independently selected from C2-C6 alkenyl or C1-C6 alkyl, wherein the alkenyl or alkyl is optionally further replaced by one or more hydroxyl or halogen groups.

[0018] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R4é F ouF

[0019] A preferred solution of the present invention provides a compound as shown by general formula (I), (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R4 is Petition 870250081292, dated 10 / 09 / 2025, page 24 / 258 11 / 79

[0020] In a preferred embodiment of the present invention, the compound as shown by general formula (I), (II) or (III) is selected from: Petition 870250081292, dated 10 / 09 / 2025, page 25 / 258 12 / 79 Petition 870250081292, dated 10 / 09 / 2025, page 26 / 258 13 / 79 Petition 870250081292, dated 10 / 09 / 2025, page 27 / 258 14 / 79

[0021] In a further preferred embodiment of the present invention, the compound as shown by general formula (I), (II) or (III) is selected from: Compound serial number Structure Name Example 1 9. 1 l · il 0 NFHO N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 2 0 fTj h VUr- F Η O N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl1-oxoisoindolin-5-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 3 c, Λ cr •'Air H 0 4-(ethylsulfonamido)-N-(7-(piperidin-1-yl)2,3-dihydrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamide Petition 870250081292, dated 10 / 09 / 2025, page 28 / 258 15 / 79 Compound Serial Number Structure Name Example 4 O., . Õ V Ho N-(7-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-5-yl)-4(ethylsulfonamide)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 5 °)' .o 'V N-(7-(3,3-difluoropyrrolidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 6 Lll 0 NFN '' H ° N-(7-(3,3-difluoroazetidine-1-yl)-2,3-di- hydrobenzofuran-5-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 7 9. Λ til fi'0 / N ……. 4-(cyclopropanosulfonamide)-N-(7(4,4-difluoropyridine-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 8 V ° <1 !%Λ N-(7-cyclopropyl-2,3-di-hydrobenzofuran5-yl)-4-(ethylsulfonamide)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 9 Co / W ° ZI ZI ry) Ό \= / 4-(ethylsulfonamido)-N-(7-(2-methylprop-1en-1-yl)-2,3-di-hydrobenzofuran-5-yl)-2(6-azaspiro[2.5]octan-6-yl)benzamide Petition 870250081292, dated 10 / 09 / 2025, p. 29 / 258 16 / 79 Compound Serial Number Structure Name Example 10 or 5 Ο N °s- H ° 4-(ethylsulfonamide)-N-(7-isobutyl-2,3-dihydrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-1pÕda 10-yl)benza NFHO N-(7-(4,4-difluoro-1-hydroxycyclo-hexyl)- 2,3-di-hydrobenzofuran-5-yl)-4(ethylsulfonamide)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example *Ο= 12 °—J o ZI / Λ 4-(cyclopropanosulfonamide)-N-(7(4,4-difluoro-1-hydroxycyclo-hexyl)-2,3-dihydrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamide , Sample N 13 l N-(7-(4,4-difluoropiperidine-1yl)benzo[d][1,3]dioxol-5-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 14 a or οογΑa? N-(8-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4(ethylsulfonamide)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 15 A- ·òc-' N-(8-(4,4-difluoropiperidine-1-yl)dihydrobenzofuran-6-yl)-4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Petition 870250081292, dated 10 / 09 / 2025, p. 30 / 258 17 / 79 Compound Serial Number Structure Name Example 16 n-nZ ri °CnJ / 9-3⁄4VF HO N-(4-(4,4-difluoropiperidin-1 -yl)-1 -methyl1H-indazol-6-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 17 y, . Õ N-(4-(4,4-difluoropiperidine-1-yl)-2-methyl2H-indazol-6-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 18 1 11 0 N V. F N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl2H-indazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 19 -Oy Ò ℓ N· Lã 11 F 0 N-(7-(4,4-difluoropiperidin-1 -yl)-1 -methyl1H-indazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 20 n-nh <9 ri °C unJvF N-(4-(4,4-difluoropiperidine-1 -yl)-1Hindazol-6-yl)-4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 21 γ^ί HNx l· li - UT 0 NH N-(7-(4,4-difluoropiperidin-1 -yl)-1Hindazol-5-yl)-4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide Petition 870250081292, dated 10 / 09 / 2025, p. 31 / 258 18 / 79 Compound Serial Number Structure Name Example 22 r ii 0 N Xjn N-(7-(4,4-difluoropiperidin-1-yl)-2methylbenzo[d]oxazol-5-yl)-4(ethylsulfonamide)-2-(6azas)yloemploetanzamide[2-2.5] 1Ν~ϊ Π fll 0 FHO N-(7-(4,4-difluoropiperidin-1 -yl)-1 oxoisoindolin-5-yl)-4-(ethylsulfonamide)2-(6-azaspiro[2.5]octan-6-yl U)benzamide 1 Õ Example-1 24 1 ' ΓΛ H 0 N-(7-(3,3-difluoroazetidine-1-yl)-2-methyl2H-indazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 25 ' 5 N-(7-(3,3-difluoropyrrolidin-1-yl)-2-methyl2H-indazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide Example 26 sy > on 7......- 4-(cyclopropanosulfonamide)-N-(7(4,4-difluoropyridin-1-yl)-2-methyl-2Hindazol-5-yl)-2-(6-azaspiro[2.5]octan-6yl)benzamide Example 27 Γ1 HO C JÚ> 4-(ethylsulfonamide)-N-(2-methyl-7morpholino-1-oxoisoindolin-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamide Petition 870250081292, dated 10 / 09 / 2025, p. 32 / 258 19 / 79 Compound serial number Structure Name Example 28 O ,o °' ZI '° • / . N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl1-oxoisoindolin-5-yl)-4-((2hydroxyethyl)sulfamine)-2-(6azaspiro[2.5]octan-6-yl)benzamide Example 29 on ° NF 1 \ HL Ã S^0HF H ° N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-((2hydroxyethyl)sulfamine)-2-(6azaspiro[2.5]octan-6-yl)benzamide or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt.

[0022] Note: if there is a difference between the structure drawn and the name given to the structure, the structure drawn shall take precedence.

[0023] Additionally, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition contains an effective amount of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, an excipient or a combination thereof.

[0024] The present invention provides the use of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) as a medicament (for use in treatment).

[0025] The present invention provides the use of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer Petition 870250081292, dated 10 / 09 / 2025, page 33 / 258 20 / 79 of the same or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) in the preparation of a KIF18A inhibitor.

[0026] The present invention further provides the use of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) in the preparation of a medicament for treating a KIF18A-mediated disease, wherein the KIF18A-mediated disease is preferably a cancer; wherein the KIF18A-mediated disease is more preferably selected from a hepatocellular carcinoma, a glioblastoma, a colon cancer, a breast cancer, a lung cancer, a cholangiocarcinoma, a pancreatic cancer, a prostate cancer, a bladder cancer, a head cancer, a neck cancer, a cervical cancer, an ovarian cancer, a synovial sarcoma, a rhabdomyosarcoma, a colorectal cancer and a pulmonary adenocarcinoma.

[0027] The present invention further provides the use of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) in the preparation of a medicament for treating cancer.

[0028] The present invention provides the use of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) in the preparation of a medicament for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, Petition 870250081292, dated 10 / 09 / 2025, page 34 / 258 21 / 79 one cervical cancer, one ovarian cancer, one synovial sarcoma, one rhabdomyosarcoma, one colorectal cancer, and one lung adenocarcinoma.

[0029] The present invention further provides a method for preventing and / or treating a KIF18A-mediated disease, comprising administering an effective amount of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) to a patient; wherein the KIF18A-mediated disease is preferably cancer; wherein the KIF18A-mediated disease is more preferably selected from a hepatocellular carcinoma, a glioblastoma, a colon cancer, a breast cancer, a lung cancer, a cholangiocarcinoma, a pancreatic cancer, a prostate cancer, a bladder cancer, a head cancer, a neck cancer, a cervical cancer, an ovarian cancer, a synovial sarcoma, a rhabdomyosarcoma, a colorectal cancer and a pulmonary adenocarcinoma.

[0030] The present invention further provides a method for preventing and / or treating cancer, comprising administering an effective amount of the compound as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof, or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) to a patient.

[0031] The present invention further provides a method for preventing and / or treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer or pulmonary adenocarcinoma, comprising administering an effective amount of the compound Petition 870250081292, dated 10 / 09 / 2025, page 35 / 258 22 / 79 as shown by general formula (I), (II) or (III), or of the stereoisomer thereof, of the tautomer thereof or of the pharmaceutically acceptable salt thereof or of the pharmaceutical composition thereof (such as the pharmaceutical composition described in the technical section above) to a patient. DETAILED DESCRIPTION

[0032] Unless stated otherwise, some terms used in the descriptive report and claims of the present invention are defined as follows.

[0033] “Linkage” refers to the fact that an identified substituent does not exist, and two substituent end parts are directly connected to form the linkage.

[0034] “Alkyl” refers to an aliphatic hydrocarbon group comprising a linear or branched C1-C20 chain when taken as a group or part of a group. Preferably, the alkyl is C1-C10 alkyl, and more preferably, the alkyl is C1-C6 alkyl. The embodiments of an alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted.

[0035] “Alkenyl” refers to alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. Preferably, the alkenyl group is C2-C4 alkenyl. The alkenyl group may be optionally substituted or not substituted.

[0036] “Alkynyl” refers to an aliphatic hydrocarbon group containing Petition 870250081292, dated 10 / 09 / 2025, p. 36 / 258 23 / 79 a carbon-carbon triple bond and can be a linear chain or a branched chain. Preferably, the alkynyl group is C2-C10 alkynyl, more preferably, the alkynyl group is C2-C6 alkynyl, and most preferably, the alkynyl group is C2-C4 alkynyl. Embodiments of an alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like. The alkynyl group may be substituted or unsubstituted.

[0037] Alkylene refers to a saturated linear or branched aliphatic hydrocarbon group C1-C20, having 2 residues derived by the removal of two hydrogen atoms from the same carbon or two different carbon atoms from the parent alkane, and is preferably C1-C10 alkylene, and more preferably C1-C6 alkylene. Embodiments of an alkylene group include, but are not limited to, methylene, 1,1-ethylidene, 1,2-ethylidene, 1,1-propylidene, 1,2-propylidene, 1,3-propylidene, 1,4-butylidene and the like. The alkylene may be substituted or unsubstituted.

[0038] Cycloalkyl refers to a non-aromatic cyclic alkyl group, wherein one or more ring-forming atoms are carbon atoms; “cycloalkyl” comprises a monocyclic ring, a polycyclic ring, a fused ring, a bridging ring and a spirocyclic ring, and preferably comprises a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring. Embodiments of a cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl and the like. Cycloalkyl may be substituted or unsubstituted.

[0039] Spiroalkyl refers to a 5-18 membered polycyclic group with two or more cyclic structures, and single rings sharing a carbon atom (called a spiro atom) between them, and the ring containing one or more double bonds, but no ring has a fully conjugated π-electron aromatic system. Preferably, spiroalkyl is a 6- to 14 membered group, and more preferably, spiroalkyl is a 7- to 10 membered group. Spiroalkyl is divided into mono-, di- or multispiroalkyl according to the number of spiro atoms shared between rings, is Petition 870250081292, dated 10 / 09 / 2025, page 37 / 258 24 / 79 preferably mono- and diespiroalkyl, and preferably is 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered. Non-limiting embodiments of spiroalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl and the like.

[0040] Fused cycloalkyl refers to a 5-18 membered complete carbon polycyclic group with two or more cyclic structures sharing a pair of carbon atoms between them, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron aromatic system. Preferably, the fused cycloalkyl is a 6- to 12 membered group, and more preferably, the fused cycloalkyl is a 7- to 10 membered group. The fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings. The fused cycloalkyl is preferably bicyclic or tricyclic fused cycloalkyl, and is more preferably 5-membered / 5-membered or 5-membered / 6-membered bicycloalkyl. Non-limiting embodiments of fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl1-alkenyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetrahydrophenyl and the like.

[0041] Bridged cycloalkyl refers to a 5-18 membered complete carbon polycyclic group with two or more cyclic structures sharing two non-directly bonded carbon atoms, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron aromatic system. Preferably, the bridged cycloalkyl is a 6- to 12 membered group, and more preferably, the bridged cycloalkyl is a 7- to 10 membered group. Preferably, the bridged cycloalkyl is a 6- to 14 membered group, and more preferably, the bridged cycloalkyl is a 7- to 10 membered group. The bridged cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of rings. Petition 870250081292, dated 10 / 09 / 2025, p. 38 / 258 25 / 79 constituents, the bridged cycloalkyl is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and is more preferably a bicyclic or tricyclic bridged cycloalkyl. Non-limiting embodiments of the bridged cycloalkyl include, but are not limited to, (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)bicyclo[3.3.2]decyl and the like.

[0042] “Heterocyclyl”, “heterocycloalkyl”, heterocycle or heterocyclic may be used interchangeably in the present application, and each refers to a non-aromatic heterocyclyl, in which one or more ring-forming atoms are selected from heteroatoms: nitrogen, oxygen or S(O)t (where t is selected from 0, 1 or 2). The heterocyclyl comprises a monocyclic ring, a polycyclic ring, a fused ring, a bridging ring and a spirocyclic ring. Preferably, the heterocyclyl is a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Embodiments of “heterocyclyl” include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexa-. hydropyrimidine, and similar things.

[0043] The heterocycline group can be substituted or unsubstituted.

[0044] “Spiro-heterocyclilla refers to a polycyclic group of 5-18 members Petition 870250081292, dated 10 / 09 / 2025, page 39 / 258 26 / 79 with two or more cyclic structures, and the simple rings sharing one atom between them, and the ring containing one or more double bonds, but no ring having a fully conjugated π-electron aromatic system, in which one or more ring atoms are selected from heteroatoms: nitrogen, oxygen, or S(O)t (where t is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, the spiro-heterocyclyl group is 6 to 14 members, and more preferably, the spiro-heterocyclyl group is 7 to 10 members. The spiro-heterocyclyl group is divided into mono-, di-, or multispiro-heterocyclyl groups according to the number of spiro atoms shared between rings.Spiro-heterocyclyl is preferably mono- and diespiro-heterocyclyl, and is most preferably monospiro-heterocyclyl with 4 members / 4 members, 4 members / 5 members, 3 members / 5 members, 3 members / 6 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members. Non-limiting embodiments of spiro-heterocyclyl include, but are not limited to, 1,7-dioxane[4.5]decyl, 2-oxa-7azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl, H,. V and similar.

[0045] “Fused heterocycline refers to a complete carbon polycyclic group with two or more cyclic structures sharing a pair of atoms between them, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from heteroatoms: nitrogen, oxygen or S(O)t (wherein t is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably, the fused heterocycline is a 6 to 14 membered group, and more preferably, the fused heterocycline is a 7 to 10 membered A group. Petition 870250081292, dated 10 / 09 / 2025, p. 40 / 258 27 / 79 fused heterocyclyls can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyls according to the number of constituent rings. The fused heterocyclyl is preferably a bicyclic or tricyclic fused heterocyclyl, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting embodiments of the fused heterocyclyl include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin and the like.

[0046] “Bridged heterocycline refers to a 5-18 membered polycyclic group with two or more cyclic structures sharing two atoms not directly fixed to each other, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from heteroatoms: nitrogen, oxygen or S(O)t (where t is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably, the bridged heterocycline is a 6- to 14 membered group, and more preferably, the bridged heterocycline is a 7- to 10 membered group. The bridged heterocycline can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclines according to the number of constituent rings.A bridging heterocycline is preferably a bicyclic, tricyclic, or tetracyclic bridging heterocycline, and is most preferably a bicyclic or tricyclic bridging heterocycline. Non-limiting embodiments of bridging heterocyclines include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl, and the like.

[0047] Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl is C6-C10 aryl, more preferably, the aryl is phenyl and naphthyl, and most preferably, the aryl is naphthyl. The aryl group may be substituted or unsubstituted. Petition 870250081292, dated 10 / 09 / 2025, p. 41 / 258 28 / 79

[0048] Heteroaryl refers to a 5-6 membered aromatic monocyclic ring or an 8-10 membered aromatic bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur.As the modalities of “heteroarila” understand, but are not limited to, a, furila, pyridila, 2-oxo-1,2-di-hidropiridila, piridazinila, pirimidinila, pirazinila, thienila, isoxazolila, oxazolila, oxadiazolila, imidazolila, pyrrolila, pirazolila, triazolila, tetrazolila, tiazolila, isotiazolila, 1,2,3-tiadiazolila, benzodioxolila, benzotiofenila, benzimidazolila, indolila, isoindolila, 1,3-dioxo-isoindolila, quinolila, indazolila, benzistioazolila, benzoxazolila, benzisoxazolila, isotiazolila, 1H-1,2,4-triazolila, 4H-1,2,4-triazolila, piridila, pirimidinila, pirazina-2(1H)-ceto, pirimidina-4(3H)-ceto, piridazina-3(2H)-ceto, 1H-indolila, 1H-benzo[d]imidazolila, 1H-pirrolo[2,3c]piridila, 3H-imidazo[4,5-c]piridila, isoquinolinila, quinazolinila, 2H-isoindolila, furan[3,2-b]piridila, furan[2,3-c]piridila, tieno[2,3-c]piridila, benzofurila,. benzo[b]tienila, 1H-pyrrolo[3,2-b]piridila, 2H-pyrrolo[3,4-c]piridila, N=^ N-NH and similar.

[0049] The heteroaryl may be substituted or not substituted.

[0050] Alkoxy refers to an “alkyl-O-” group. Alkyl is defined herein. C1-C6 alkoxy is preferred. Embodiments of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like. Petition 870250081292, dated 10 / 09 / 2025, p. 42 / 258 29 / 79

[0051] Nitro refers to a -NO2 group.

[0052] Hydroxyl refers to an -OH group.

[0053] Halogen refers to fluorine, chlorine, bromine and iodine.

[0054] Amino refers to -NH2.

[0055] Cyan refers to -CN.

[0056] Benzyl refers to -CH2-phenyl.

[0057] Carboxyl refers to -C(O)OH.

[0058] Carboxylate group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0059] Hydroxyalkyl refers to alkyl substituted with hydroxyl, where the alkyl is as defined above.

[0060] Aminoalkyl refers to alkyl substituted by amino, wherein the alkyl is as defined above.

[0061] Halogenated alkyl refers to halogen-substituted alkyl, wherein the alkyl is as defined above.

[0062] Halogenated alkoxy refers to alkoxy substituted with halogen, wherein the alkoxy is as defined above.

[0063] DMSO refers to dimethyl sulfoxide.

[0064] “BOC refers to tert-butoxycarbonyl.

[0065] “Bn” refers to benzyl.

[0066] THP refers to 2-tetrahydropyranyl.

[0067] TFA refers to trifluoroacetic acid

[0068] Ts refers to p-toluenesulfonyl.

[0069] “Leaving group”, or leaving group, is an atom or functional group detached from a larger molecule in a chemical reaction, a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, a reactant attacked by a nucleophilic reactant is called a substrate, and an atom or atomic group broken off along with an electron pair from a substrate molecule is called a leaving group. A group that readily accepts electrons and carries Petition 870250081292, dated 10 / 09 / 2025, page 43 / 258 30 / 79 strongly negative charges is a good leaving group. When the pKa of a conjugate acid's leaving group is lower, the leaving group is easier to separate from other molecules. This is because when the pKa of the conjugate acid is lower, the corresponding leaving group does not need to combine with other atoms, and the tendency for existence in anion form (or electrically neutral leaving group) is also enhanced. Common leaving groups include, but are not limited to, halogens, methanesulfonyls, OTs, or -OH.

[0070] Substituted refers to those in which one or more hydrogen atoms, preferably a maximum of 5 hydrogen atoms, and more preferably 1 to 3 hydrogen atoms, in a group, are independently substituted by a corresponding number of substituents. It may be assumed that the substituents are only in their possible chemical positions, and those skilled in the art may determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, hydrogen-free amino or hydroxyl groups may be unstable when combined with carbon atoms with unsaturated bonds (such as olefins).

[0071] Substitution or replaced in the descriptive report, unless otherwise specified, refers to the group that may be replaced by one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiol, heterocycloalkylthiol, amino, halogenated alkyl, hydroxyalkyl, carboxyl, carboxylate group, =O, -OR6, -C(O)R6, -C(O)OR6, -NHC(O)R6, -NHC(O)OR6, -NR7R8, C(O)NR7R8, -CH2NHC(O)OR6, -CH2NR7R8 or -S(O)rR6;

[0072] R6 is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, Petition 870250081292, dated 10 / 09 / 2025, p. 44 / 258 31 / 79 heterocyclyl, aryl, heteroaryl, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR10R11, C(O)NR10R11, -SO2NR10R11 or -NR10C(O)R11;

[0073] R7 and R8 are each independently selected from a hydrogen, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl atom, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R9, C(O)OR9, -OC(O)R9, -NR10R11, -C(O)NR10R11, -SO2NR10R11 or -NR10C(O)R11;

[0074] or, R7 and R8 form a 4-8 membered heterocycline together with the atoms to which R7 and R8 are attached, wherein the 4-8 membered heterocycline contains one or more N, O or S(O)r, and the 4-8 membered heterocycline is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycline, aryl, heteroaryl, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, NR10R11, -C(O)NR10R11, -SO2NR10R11 or -NR10C(O)R11;

[0075] R9, R10 and R11 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate group.

[0076] r is selected from 0, 1 or 2.

[0077] The compound of the present invention may contain an asymmetric center or a chiral center, thus existing in different stereoisomeric forms. It is expected that all stereoisomeric forms of the compound of the present invention comprise, but are not limited to, a diastereomer, an enantiomer and an atropisomer and a geometric (conformational) isomer and a mixture thereof, such as a racemic mixture, all of which are included within the scope of the present invention. Petition 870250081292, dated 10 / 09 / 2025, page 45 / 258 32 / 79

[0078] Unless otherwise specified, the structure described in the present invention further comprises all isomers of that structure (such as forms of a diastereomer, an enantiomer and an atropisomer and a geometric (conformational) isomer; such as the R and S configurations of asymmetric centers, double bond isomers (Z) and (E) and conformational isomers (Z) and (E)). Therefore, a single stereoisomer and an enantiomeric mixture, a diastereomeric mixture and a geometric (conformational) isomer mixture of the compound of the present invention are all included within the scope of the present invention.

[0079] Pharmaceutically acceptable salt refers to some salts of the above compounds capable of retaining original biological activity and suitable for medical use. The pharmaceutically acceptable salt of the compound as shown by general formula (I) may be a metallic salt or an amine salt formed with a suitable acid.

[0080] Pharmaceutical composition refers to a mixture containing one or more compounds described herein or their physiologically acceptable salts or prodrugs and other chemical components, and other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to organisms, which is beneficial for the absorption of active ingredients, thus exerting biological activity. METHOD OF SYNTHESIS FOR COMPOUND OF THE PRESENT INVENTION

[0081] In order to achieve the objective of the present invention, the following technical solution is used in the present invention.

[0082] The present invention provides a method of preparation for the compound as shown by general formula (I), or the stereoisomer thereof, the tautomer thereof or the pharmaceutically acceptable salt thereof, and the method comprises: Petition 870250081292, dated 10 / 09 / 2025, page 46 / 258 33 / 79 G (IA) (IB) (I) perform a condensation reaction on a compound as shown by general formula (IA) and a compound as shown by general formula (IB), and optionally additionally perform a substitution reaction to obtain the compound as shown by general formula (I), wherein: the L2 is selected from der3; Y is selected from hydroxyl or chlorine; and the ring definitions A, X1, X2, Y1, Y2, Y3, L1, G, R1, R3, R4, Rae n are as described in the general formula (I). MODALITIES

[0083] The present invention is further described in combination with the following embodiments, but these embodiments are not intended to limit the scope of the present invention. EXAMPLES

[0084] The preparation of a representative compound as shown by formula (I) and the related structural identification data are given in the examples. It should be noted that the following embodiments are used to illustrate the present invention and are not intended to limit the present invention. A 1H NMR spectrum is measured by a Bruker instrument (400 MHz), and a chemical shift is represented by ppm. Tetramethylsilane is used as an internal standard (0.00 ppm). In a 1H NMR representation method: s = single peak, d = double peak, t = triple peak, m = multiple peak, br = extended, dd = double peak of double peak, and dt = double peak of triple peak. When a constant Petition 870250081292, dated 10 / 09 / 2025, page 47 / 258 34 / 79 coupling is provided, the unit of the coupling constant is Hz.

[0085] A mass spectrum is measured by an LC / MS instrument, and an ionization mode can be ESI or APCI.

[0086] A silica gel plate used for thin-layer chromatography is a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate; the silica gel plate used for thin-layer chromatography (TLC) adopts a specification of 0.15 mm~0.2 mm, and a product separated and purified by thin-layer chromatography adopts a specification of 0.4 mm~0.5 mm.

[0087] Yantai Huanghai silica gel 200~300 mesh is generally used in column chromatography.

[0088] In the following examples, unless otherwise specified, all temperatures are Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available raw materials and reagents are used directly without further purification. Unless otherwise specified, manufacturers of commercially available raw materials and reagents include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., Jingyan Chemical Technology Co., Ltd., etc. CD3OD: deuterated methanol. CDCl3: deuterated chloroform. DMSO-d6: deuterated dimethyl sulfoxide.

[0089] Argon atmosphere means that a reaction bottle is connected to an argon flask with a volume of about 1 l.

[0090] Unless otherwise specified in the embodiments, a solution in the reaction refers to an aqueous solution.

[0091] The compound is purified by silica gel column chromatography and reversed-phase column chromatography, in which an eluent system is selected from system A: petroleum ether and acetate system Petition 870250081292, dated 10 / 09 / 2025, page 48 / 258 35 / 79 ethyl; system B: dichloromethane and methanol system; system C: dichloromethane and ethyl acetate system; and system D: aqueous solution of trifluoroacetic acid and acetonitrile system. A solvent volume ratio varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine. Example 1 N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamido)2-(6-azaspiro[2.5]octan-6-yl)benzamide First stage 7-Bromo-5-nitro-2,3-dihydrobenzofuran

[0092] Nitric acid (1.5 ml) was added dropwise to a solution of 7-bromo-2,3-dihydrobenzofuran 1a (700 mg, 3.52 mmol, commercially available) in trifluoroacetic acid (3 ml) and stirred at room temperature for 2 hours. LCMS showed that the reaction was complete, and the reaction mixture was Petition 870250081292, dated 10 / 09 / 2025, page 49 / 258 36 / 79 added to water (50 ml) dropwise slowly to precipitate a light yellow solid. After filtration, the filter cake was vacuum dried to obtain 7-bromo5-nitro-2,3-dihydrobenzofuran 1b (750 mg), with a yield of 87.39%.

[0093] MS m / z (ESI): 244.0 [M+1]. Second stage 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine

[0094] 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b (650 mg, 2.66 mmol) and 4,4-difluoropiperidine 1c (645.24 mg, 5.33 mmol) were dissolved in toluene (20 ml), then palladium acetate (59.80 mg, 266.35 μmol), R-(+)-1,T-binaphthyl-2,2'-bis(diphenylphosphine) (497.54 mg, 799.04 μmol) and cesium carbonate (2.60 g, 7.99 mmol) were added, and the mixture was subjected to argon substitution 3 times, heated to 100 °C and stirred for 16 hours. After the reaction was complete, water (30 ml) was added and extracted with dichloromethane (20 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7yl)piperidine 1d (610 mg), with a yield of 80.57%.

[0095] MS m / z (ESI): 285.1 [M+1]. Third stage 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine

[0096] Ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a mixed solution of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 1d (300 mg, 1.06 mmol) in water (20 ml) and ethanol (20 ml). The mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, it was filtered, and ethyl acetate (30 ml) was added for extraction. The water phase was further extracted with ethyl acetate (30 ml x 2), and the combined organic phase was washed with saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran. Petition 870250081292, dated 10 / 09 / 2025, page 50 / 258 37 / 79 5-amine 1e (220 mg), with a yield of 81.98%.

[0097] MS m / z (ESI): 255.1 [M+1]. Fourth stage N-(7-(4,4-difluoropiperidin-1-yl)-2,3-di-hidrobenzofuran-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamida

[0098] 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 1e (68.34 mg, 268.77 μmol), 2-(6-azaspiro[2.5]octano-6-yl)-4-iodobenzoic acid 1f (80 mg, 223.97 μmol, prepared according to the method in published patent WO2020132648) and 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 ml), and stirred at room temperature for 30 minutes, then (chloro(dimethylamino)methylene)dimethylammonium hexafluorophosphate (188.53 mg, 671.92 μmol) was added to the mixture and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain N-(7(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide 1 g (92 mg), with a yield of 69.22%.

[0099] MS m / z (ESI): 594.4 [M+1]. Fifth stage N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamido)2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0100] N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide 1 g (80 mg, 134.81 μmol), ethyl sulfonamide 1 h (22.07 mg, 202.21 μmol, commercially available), 2-(methylamino)acetic acid (18.01 mg, 202.21 μmol), cuprous iodide (7.70 mg, 40.44 μmol), and potassium phosphate trihydrate (179.50 mg, 674.03 μmol) were added to N,N-dimethylformamide (2 ml), and the mixture was purged with argon, then heated to 100 °C, and stirred. for 6 hours. After the reaction was complete, it was filtered, and the filtrate was purified by a preparative liquid phase (AKZONOBEL Kromasil separation column; 250*21.2 mm ID; 5 Petition 870250081292, dated 10 / 09 / 2025, page 51 / 258 38 / 79 pm, 20 mL / min; mobile phase A: 0.05% of TFA+H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidine-1-yl)-2,3-di-hydrobenzofuran-5-yl)-4(ethylsulfonamide)-2-o)1oczamide-azas5- (31 mg), with an urn yield of 40.02%.

[0101] MS m / z (ESI): 575.3 [M+1].

[0102] 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.14 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 1.8 Hz, J, 1,1 (1H), 7.07–7.01 (m, 2H), 4.54 (d, J = 8.7 Hz, 2H), 3.19 (qd, J = 8.7, 7.2, 4.1 Hz, 8H), 2.97 (t, J = 5.2 Hz, 4H), 8, J = 1 1.55 (t, J = 5.1 Hz, 4H), 1.20 (t, J = 7.3 Hz, 3H), 0.35 (s, 4H). Example 2 N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindolin-5-yl)-4-(ethylsulfonamido) 2-(6-azaspiro[2.5]octan-6-yl)benzamide First step 4-Bromo-2-fluoro-6-methylbenzoate

[0103] 4-bromo-2-fluoro-6-methylbenzoic acid 2a (1.0 g, 4.29 mmol, commercially available) and potassium carbonate (1.19 g, 8.58 mmol) were dissolved in N,N-dimethylformamide (10 ml), methyl iodide (913.63 mg, 6.44 Petition 870250081292, dated 10 / 09 / 2025, page 52 / 258 A concentration of 39 / 79 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 hours. After the reaction was complete, water (20 ml) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 4-bromo-2-fluoro-6-methylbenzoate 2b (1.03 g), with a yield of 97.15%.

[0104] MS m / z (ESI): 247.0 [M+1].

[0105] 1H RMN (400 MHz, DMSO-d6) δ 7,54 (dd, J = 9,5, 1,8 Hz, 1H), 7,46 (d, J = 1,8 Hz, 1H), 3,87 (s, 3H), 2,33 (s, 3H). Second stage: Methyl 4-Bromo-2-(bromomethyl)-6-fluorobenzoate

[0106] Methyl 4-Bromo-2-fluoro-6-methylbenzoate 2b (500 mg, 2.02 mmol) and azodi-isobutyronitrile (33.23 mg, 202.38 μmol) were dissolved in acetonitrile (10 ml), then N-bromosuccinimide (468.26 mg, 2.63 mmol) was added at room temperature. The resulting mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, water (20 ml) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 ml*2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate 2c (0.53 g), with a yield of 80.34%.

[0107] MS m / z (ESI): 326.9 [M+1]. Third step: 5-Bromo-7-fluoro-2-methylisoindolin-1-one

[0108] 4-Bromo-2-(bromomethyl)-6-fluorobenzoate methyl 2c (500 mg, 1.53 mmol) was dissolved in methylamine dioxane solution (4 M, 3.83 ml), heated to 40 °C and stirred for 2 hours. After the reaction was complete, Petition 870250081292, dated 10 / 09 / 2025, page 53 / 258 40 / 79 water (20 ml) was added dropwise to the reaction mixture, and the resulting system was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-fluoro-2-methylisoindolin-1-one 2d (130 mg), with a yield of 34.72%.

[0109] MS m / z (ESI): 244.0 [M+1]. Fourth stage 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one

[0110] 5-Bromo-7-fluoro-2-methylisoindolin-1-one 2d (120 mg, 491.68 μmol) and 4,4-difluoropiperidine 1c (9.93 mg, 81.95 μmol) were dissolved in dimethyl sulfoxide (5 ml), then N,N-diisopropylethylamine (158.87 mg, 1.23 mmol) was added, heated to 150 °C and stirred for 8 hours. After the reaction was complete, water (20 ml) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one 2e (150 mg), with a yield of 88.38%.

[0111] MS m / z (ESI): 344.8 [M+1]. Fifth step (tert-butyl 7-(4,4-Difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)carbamate

[0112] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one 2e (140 mg, 405.58 μmol) and tert-butyl carbamate (95.02 mg, 811.17 μmol) were dissolved in 1,4-dioxane (10 ml), then palladium acetate (9.11 mg, 40.56 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (46.94 mg, 81.12 μmol) and cesium carbonate (396.44 mg, 1.22 mmol) were added, and the mixture was bubbled with argon for 5 minutes, heated to 100 °C and Petition 870250081292, dated 10 / 09 / 2025, page 54 / 258 41 / 79 stirred for 18 hours. After the reaction was complete, water (20 ml) was added dropwise to the reaction mixture and the resulting mixture was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl (7-(4,4-difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)carbamate 2f (150 mg), with a yield of 96.96%.

[0113] MS m / z (ESI): 382.0 [M+1]. Sixth stage 5-Amino-7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one

[0114] tert-butyl (7-(4,4-Difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)carbamate 2f (150 mg, 393.27 μmol) was dissolved in hydrochloric acid (4 M, 983.18 μl), heated to 60 °C and stirred for 16 hours. After the reaction was complete, water (20 ml) and ethyl acetate (20 ml) were added sequentially to the reaction mixture. A pH value was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 5amino-7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one 2g (110 mg), with a yield of 99.43%.

[0115] MS m / z (ESI): 281.9 [M+1]. Seventh stage N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide

[0116] 2-(6-azaspiro[2.5]octane-6-yl)-4-iodobenzoic acid 1f (130 mg, 363.96 μmol) was dissolved in acetonitrile (10 ml), then 1-methylimidazole (60.50 mg, 727.91 μmol) and tetramethylchloroformamidin hexafluorophosphate (204.24 mg, 727.91 μmol) were added and stirred at room temperature for 1 hour. 5-amino-7-(4,4-difluoropiperidin-1-yl)-2-methylisoindolin-1-one 2g (112.62 mg, 400.35 μmol) was added, and the resulting mixture was heated to 60 °C and stirred. Petition 870250081292, dated 10 / 09 / 2025, page 55 / 258 42 / 79 for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2h (180 mg), with a yield of 79.71%.

[0117] MS m / z (ESI): 620.8 [M+1]. Eighth stage N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)-4-(ethylsulfonamido)2-(6-azaspiro[2.5]octan-6-yl)benzamida

[0118] N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl-1-oxoisoindolin-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide 2h (100 mg, 161.17 μmol) and ethyl sulfonamide 1h (35.18 mg, 322.34 μmol) were dissolved in N,N-dimethylformamide (10 ml), then cuprous iodide (17.89 mg, 80.58 μmol), 2-(methylamino)acetic acid (14.36 mg, 161.17 μmol) and potassium phosphate trihydrate (214.60 mg, 805.84 μmol) were added, and the mixture was subjected to bubbling with argon for The mixture was heated to 100 °C for 5 minutes and stirred for 18 hours. After the reaction was complete, water (20 ml) was added dropwise to the reaction mixture, and the resulting system was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a preparative liquid phase (AKZONOBEL Kromasil separatory column; 250^21.2 mm ID).; 5 μm, 20 ml / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidin-1-yl)-2-methyl-1oxoisoindolin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[ (45.3 mg), with a yield of 45.92%.

[0119] MS m / z (ESI): 602.3 [M+1].

[0120] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.18 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J = 2.1Hz, 1Hz, 7.1Hz), 1H), 7.05 (dd, J = 8.5, 2.1 Hz, 1H), 4.37 (s, 2H), 3.20 (q, J = 7.3 Hz, 2H),3.30(m, 4H), 3.00 (s, 3H), 2.97 (t, J = 5,3 Hz, 2.4 Hz), J 25.7, 18.1,8.9 Hz, 4H), 1.55 (t, J = 5.3 Hz, Petition 870250081292, of 10 / 09 / 2025, p. 56 / 258 43 / 79 4H), 1.21 (t, J = 7.3 Hz, 3H), 0.34 (s, 4H). Example 3 4-(Ethylsulfonamide)-N-(7-(piperidin-1-yl)-2,3-di-hydrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamide First stage 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0121] 2-(6-azaspiro[2.5]octane-6-yl)-4-iodobenzoic acid 1f (1.0 g, 2.80 mmol) and ethyl sulfonamide 1h (458.36 mg, 4.20 mmol) were dissolved in N,N-dimethylformamide (10 ml), then cuprous iodide (266.60 mg, 1.40 mmol), sarcosine (249.43 mg, 2.80 mmol) and potassium phosphate (3.73 g, 14.00 mmol) were added, and the mixture was purged with argon, heated to 110 °C and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 ml), and a pH value was adjusted to 6 with dilute hydrochloric acid (2 mL). The mixture was extracted with dichloromethane (200 ml x 3). The combined organic phase was washed with a saturated sodium chloride solution (50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by gel electrophoresis column chromatography. Petition 870250081292, dated 10 / 09 / 2025, page 57 / 258 44 / 79 silica (eluent: system A) to obtain 4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzoic acid 3a (0.75 g), with a yield of 79.16%.

[0122] MS m / z (ESI): 339.4 [M+1]. Second stage 1-(5-Nitro-2,3-dihydrobenzofuran-7-yl)piperidine

[0123] At room temperature, 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b (488 mg, 2.00 mmol) and piperidine (340.53 mg, 4.00 mmol) were dissolved in toluene (20 ml), then palladium acetate (44.89 mg, 199.97 μmol), R-(+)-1,1'binaftyl-2,2'-bis(diphenylphosphine) (373.54 mg, 599.90 μmol) and cesium carbonate (1.95 g, 6.00 mmol) were added, and the mixture was purged with argon 3 times, heated to 100 °C and stirred for 16 hours. Water (20 ml) was added and extracted with ethyl acetate (20 ml*3). The combined organic phase was washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 3b (310 mg), with a yield of 62%.

[0124] MS m / z (ESI): 249.1 [M+1]. Third stage 7-(Piperidin-1-yl)-2,3-dihydrobenzofuran-5-amine

[0125] At room temperature, palladium on carbon (100 mg, 805.55 μmol, 10%) was added to a solution of 1-(5-nitro-2,3-dihydrobenzofuran-7yl)piperidine 3b (0.2 g, 805.55 μmol) in methanol (20 ml), and the mixture was purged with hydrogen, then heated to 50 °C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-(piperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 3c (152 mg), with a yield of 86%. The crude product was used directly in the next reaction.

[0126] MS m / z (ESI): 219.0 [M+1]. Fourth stage 4-(Ethylsulfonamido)-N-(7-(piperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6Petition 870250081292, of 09 / 10 / 2025, page 58 / 258 45 / 79 azaspiro[2.5]octan-6-yl)benzamide

[0127] At room temperature, tetramethylchloroformamidin hexafluorophosphate (345.98 mg, 664.85 μmol), 4-(ethylsulfonamido)2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (150 mg, 443.23 μmol) and N,N-diisopropylethylamine (171.85 mg, 1.33 mmol) were added to N,N-dimethylformamide (3 ml), and stirred at room temperature for 10 minutes, then 7-(piperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 3c (116.11 mg, 531.88 μmol) was added to the mixture, heated to 65 °C and stirred for 2 hours. Water (20 ml) was added and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a preparative liquid phase (AKZONOBEL Kromasil separation column; 250 x 21.2 mm ID).; 5 μm, 20 ml / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 4-(ethylsulfonamido)-N-(7-(piperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 3 (38 mg), with a yield of 16%.

[0128] MS m / z (ESI): 539.3 [M+1].

[0129] 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 10.11 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.4, 2.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 4.50 (t, J = 8.7 Hz, 2H), 3.23 - 3.11 (m, 4H), 3.103.0 (m, 4H), 3.0-2.90 (m, 4H), 1.67-1.59 (m, 4H), 1.59-1.46 (m, 6H), 1.20 (t, J = 7.3 Hz, 3H), 0.40-0.28 (m, 4H).

[0130] Examples 4-7 were synthesized according to the synthesis methods in Examples 1-3 of the present invention. Structures and characterization data of Examples 4-7 are shown in the following table: Petition 870250081292, dated 10 / 09 / 2025, p. 59 / 258 46 / 79 Número de série e estrutura de exemplos MS m / z (ESI) 1H RMN |1 O N 1 I Η 1 II 4 H ° 565,3 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 11,55 (s, 1H), 10,13 (s, 1H), 7,82 (d, J = 8,5 Hz, 1H), 7,44 (s, 1H), 7,40 (s, 1H), 7,18 (d, J = 2,2 Hz, 1H), 7,05 (dd, J = 8,5, 2,1 Hz, 1H), 4,60 (d, J = 8,6 Hz, 2H), 3,30-3,25 (m, 4H), 3,253,10 (m, 4H), 3,05-2,89 (m, 4H), 1,66-1,4 (m, 8H), 1,21 (t, J = 7,3 Hz, 3H), 0,40-0,37 (m, 4H), 0,37-0,30 (m, 4H). IZ 01 )=o .0 °·) 561,3 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 11,52 (s, 1H), 10,11 (s, 1H), 7,82 (d, J = 8,5 Hz, 1H), 7,30 (d, J = 1,7 Hz, 1H), 7,17 (d, J = 2,1 Hz, 1H), 7,03 (dd, J = 8,5, 2,0 Hz, 1H), 6,82 (d, J = 2,0 Hz, 1H), 4,50 (t, J = 8,7 Hz, 2H), 3,70 (t, J = 13,5 Hz, 2H), 3,47 (t, J = 7,1 Hz, 2H), 3,24 - 3,11 (m, 4H), 3,05-2,90 (m, 4H), 2,44 (dt, J = 14,6, 7,1 Hz, 2H), 1,60-1,50 (m, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,40-0,28 (m, 4H). V.S Γ ll 0 N %— F 6 547.6 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 10.12 (s, 1H), 7.80 (d, J = 8.4 Hz, J = 1,5), Hz, 2H), 7.02 (dd, J = 8.5, 2.1 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 4.50 (t,. Petition 870250081292, dated 10 / 09 / 2025, p. 60 / 258 47 / 79 MS serial number and sample structure (ESI) 1H NMR J = 8.7 Hz, 2H), 4.25 (t, J = 12.3 Hz, 4H), 3.22 (m, 5H), 2.96 (t, J = 5.3 Hz), 1, 35H, 4H (t, J = 7.3 Hz, 3H), 0.36 (s, 4H). ο, δ ll 0 NF Va 7 587.3 [M+1] 1H NMR (400 MHz, DMSO-c / 6) δ 11.59 (s, 1H), 10.09 (s, 1H), 7.83 (d, J = 8, 7, Hz, = 1 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.09 (m, 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.25 (m, 6H), 2.97 (t, J = 5.3 Hz, 4H), m 2, 2,1H5 ( 1.56 (s, 4H), 0.99 (d, J = 4.6 Hz, 4H), 0.36 (s, 4H). Example 8 N-(7-cyclopropyl-2,3-di-hydrobenzofuran-5-yl)-4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide third stage First stage 7-Cyclopropyl-5-nitro-2,3-dihydrobenzofuran

[0131] At room temperature, 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b Petition 870250081292, dated 10 / 09 / 2025, page 61 / 258 48 / 79 (0.5 g, 2.05 mmol), cyclopropylboric acid (351.98 mg, 4.10 mmol), potassium phosphate trihydrate (1.64 g, 6.15 mmol), and tetrakis(triphenylphosphine)palladium (236.75 mg, 204.88 μmol) were added to a mixed solvent of ethanol (2 ml), water (2 ml), and toluene (10 ml), and the mixture was purged with argon three times, heated to 100 °C, and stirred for 16 hours. Water (20 ml) was added and extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 7cyclopropyl-5-nitro-2,3-dihydrobenzofuran 8a (255 mg), with a yield of 61%.

[0132] MS m / z (ESI): 205.9 [M+1]. Second stage 7-Cyclopropyl-2,3-dihydrobenzofuran-5-amine

[0133] At room temperature, palladium on carbon (20 mg, 1.24 mmol, 10%) was added to a solution of 7-cyclopropyl-5-nitro-2,3-dihydrobenzofuran 8a (255 mg, 1.24 mmol) in methanol (5 ml), and the mixture was purged with hydrogen and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7cyclopropyl-2,3-dihydrobenzofuran-5-amine 8b (195 mg), with a yield of 90%. The crude product was used directly in the next reaction.

[0134] MS m / z (ESI): 176.1 [M+1]. Third stage N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6yl)benzamide

[0135] A solution of 2-(6-azaspiro[2.5]octane-6-yl)-4-iodobenzoic acid 1f (0.1 g, 279.97 μmol) and N,N-dimethylformamide (0.1 ml) in dichloromethane (3 ml) was cooled by an ice bath, then oxalyl chloride (71.07 mg, 559.93 μmol) was added dropwise slowly, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue Petition 870250081292, dated 10 / 09 / 2025, page 62 / 258 49 / 79 was added to a solution of 7-cyclopropyl-2,3-dihydrobenzofuran-5-amine 8b (53.96 mg, 307.96 μmol) and triethylamine (84.99 mg, 839.90 μmol) in dichloromethane (3 ml), and the resulting mixture was stirred at room temperature for 1 hour. Water (10 ml) was added and extracted with ethyl acetate (10 ml*3). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide 8c (121 mg), with a yield of 84%.

[0136] MS m / z (ESI): 514.8 [M+1]. Fourth stage N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide

[0137] At room temperature, N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8c (150 mg, 291.60 μmol), ethyl sulfonamide 1h (47.74 mg, 437.41 μmol), 2-(methylamino)acetic acid (38.97 mg, 437.41 μmol), cuprous iodide (16.66 mg, 87.48 μmol) and potassium phosphate trihydrate (232.97 mg, 874.81 μmol) were added to N,N-dimethylformamide (2 ml), and the mixture was purged with argon, then heated to 100 °C and stirred for 6 hours. Water (20 ml) was added and extracted with ethyl acetate (10 ml*3). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative liquid phase (AKZONOBEL Kromasil separatory column; 250*21.2 mm ID; 5 μm, 20 ml / min; mobile phase A: 0.05% NH4CO3+H2O, mobile phase B: CH3CN) to obtain N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8 (18 mg), in 12% yield.

[0138] MS m / z (ESI): 495.9 [M+1].

[0139] 1H NMR (400 MHz, DMSO-de) δ 11.39 (s, 1H), 10.09 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.5, Petition 870250081292, dated 10 / 09 / 2025, p. 63 / 258 50 / 79 2.1 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 4.52 (t, J = 8.6 Hz, 2H), 3.23 - 3.09 (m, 4H), 3.0-2.90 (m, 4H), 1.91 (tt, J = 8.4, 5.2 Hz, 1H), 1.55-1.48 (m, 4H), 1.20 (t, J = 7.3 Hz, 3H), 0.97 - 0.87 (m, 2H), 0.69 - 0.61 (m, 2H), 0.37-0.31 (m, 4H).

[0140] Example 9 was synthesized according to the synthesis method in Example 8 of the present invention. The structure and characterization data of Examples 9 are shown in the following table: Series number and example structure MS m / z (ESI) 1H NMR 9-, S / 0¾ Z\ NH 0 9 510.2 [M+1] 1H NMR (400 MHz, DMSO-de) δ 11.41 (s, 1H), 10.13 (s, 1H), 7.87 - 7.75 (m, 2H), 7.18 (dd, J = 6.2, 2.1 Hz, 2H), 7.04 (dd, J = 8.5, 2.2 Hz, 1H), 6.14 (s, 1H), 4.51 (t, J = 8.7 Hz, 2H), 3.24-3.13 (m, 4H), 3.0-2.94 (m, 4H), 1.88 (s, 3H), 1.85 (s, 3H), 1.57-1.5 (m, 4H), 1.21 (t, J = 7.3 Hz, 3H), 0.37-0.3 (m, 4H). Example 10 4-(Ethylsulfonamido)-N-(7-isobutyl-2,3-di-hidrobenzofuran-5-yl)-2-(6azaspiro[2.5]octan-6-yl)benzamida

[0141] At room temperature, 4-(ethylsulfonamido)-N-(7-(2-methylprop-1-en-1 Petition 870250081292, dated 10 / 09 / 2025, pág. 64 / 258 51 / 79 il)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9 (50 mg, 98.10 pmol) and 10% palladium hydrogenation catalyst on carbon (10 mg, 98.10 pmol) were added to methanol (3 ml), and the mixture was purged with hydrogen three times, then stirred at room temperature for 4 hours. The reaction mixture was filtered, the filter cake was washed with methanol (10 ml), and the filtrate was concentrated under reduced pressure. The residue was purified by a preparative liquid phase (AKZONOBEL Kromasil separating column; 250x21.2 mm ID; 5 pm, 20 ml / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 4-(ethylsulfonamido)-N-(7-isobutyl-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 10 (2.5 mg), with a yield of 5%.

[0142] MS m / z (ESI): 512.3 [M+1],

[0143] 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.12 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H, 1H), 7.68 (d, J = 2.0 Hz, 1H, 7.1Hz), 1H), 7.12-7.00 (m, 2H), 4.49 (t, J = 8.6 Hz, 2H), 3.24-3.1 (m, 4H), 3.03-2.94 (m, 4H), 2.37 (d, J = 7.1 Hz, 2H, 9H), 1.57–1.49 (m, 4H), 1.21 (t, J = 7.3 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H), 0.37–0.31 (m, 4H). Example 11 N-(7-(4,4-difluoro-1-hydroxycyclo-hexyl)-2,3-di-hydrobenzofuran-5-yl)-4(ethylsulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)benzamide First stage Petition 870250081292, of 10 / 09 / 2025, p. 65 / 258 52 / 79 -(2,3-di-hydrobenzofuran-7-yl)-4,4-difluorocyclo-hexan-1 -ol

[0144] At -78 °C, n-butyllithium (965.44 mg, 15.07 mmol, 2.5 M) was added dropwise to a solution of 7-bromo-2,3-dihydrobenzofuran 1a (2 g, 10.05 mmol) in tetrahydrofuran (50 ml) and stirred at -78 °C for 0.5 hours. Then, 4,4-difluorocyclohexanone 11a (1.48 g, 11.05 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred at -78 °C for 0.5 hours, then heated slowly to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (20 ml), and ethyl acetate (30 ml x 2) was added for extraction. The combined organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: system A) to obtain 1-(2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol 11b (1.6 g) in a 63% yield.

[0145] MS m / z (ESI): 237.1 [M-17].

[0146] 1H NMR (400 MHz, DMSO-de) δ 7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.11 (dd, J = 7.3, 1.3 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 5.11 (s, 1H), 4.50 (t, J = 8.7 Hz, 2H), 3.13 (t, J = 8.7 Hz, 2H), -3, 2,2,4 2.04 (m, 2H), 1.96 - 1.80 (m, 2H), 1.60–1.50 (m, 2H). Second stage 4,4-Difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)cyclohexan-1-ol

[0147] At room temperature, nitric acid (2 ml) was added to a solution of 1-(2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol 11b (500 mg, 1.97 mmol) in acetic acid (5 ml) and stirred for 4 hours. Water (20 ml) was added dropwise slowly and the resulting mixture was extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7yl)cyclohexan-1-ol 11c (274 mg), with a yield of 46%.

[0148] MS m / z (ESI): 300.1 [M+1]. Petition 870250081292, dated 10 / 09 / 2025, page 66 / 258 53 / 79

[0149] 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 2.6 Hz, 1H), 8.16 - 7.88 (m, 1H), 4.75 (t, J = 8.9 Hz, 2H), 3.28 (t, J = 8.8 Hz, 2H), 2.40 (td, J = 13.7, 4.2 Hz, 2H), 2.29 - 2.07 (m, 2H), 2.00 - 1.85 (m, 2H), 1.63 - 1.49 (m, 2H). Third stage 1-(5-Amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol

[0150] At room temperature, a carbon palladium hydrogenation catalyst (20 mg, 183.78 μmol, 10%) was added to a solution of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)cyclohexan-1-ol 11c (55 mg, 183.78 μmol) in methanol (5 ml), and the mixture was purged with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol 11d (41 mg), with a yield of 83%.

[0151] MS m / z (ESI): 270.1 [M+1]. Fourth stage N-(7-(4,4-difluoro-1-hidroxycyclo-hexyl)-2,3-di-hidrobenzofuran-5-yl)-4(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamida

[0152] At room temperature, tetramethylchloroformamidin hexafluorophosphate (92.26 mg, 177.29 μmol), 4-(ethylsulfonamido)2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (40 mg, 118.20 μmol) and N,N-diisopropylethylamine (45.83 mg, 354.59 μmol) were added to N,N-dimethylformamide (3 ml), and stirred at room temperature for 10 minutes, then 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol 11d (35.01 mg, 130.02 μmol) was added to the mixture and the resulting mixture was heated to 65 °C, stirred for 2 hours. Water (10 ml) was added and the resulting mixture was extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a preparative liquid phase (AKZONOBEL Kromasil separatory column; 250 x 21.2 mm ID; 5 μm, 20 ml / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN). Petition 870250081292, dated 10 / 09 / 2025, p. 67 / 258 54 / 79 to obtain N-(7-(4,4-difluoro-1-hydroxycyclohexyl)-2,3-dihydrobenzofuran-5-yl)-4(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11 (31 mg), in 41% yield.

[0153] MS m / z (ESI): 590.3 [M+1].

[0154] 1H NMR (400 MHz, DMSO-de) δ 11.37 (s, 1H), 10.19 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 7.09 (d, J = 8.5, 2.0 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 3.30-3.13 (m, 4H), 3.13-3.0 (m, 4H), 2.39 (td, J = 13.7, 4.2 Hz, 2H), 2.31 - 2.07 (m, 2H), 1.98-1.83 (m, 2H), 1.67 - 1.52 (m, 6H), 1.21 (t, J = 7.3 Hz, 3H), 0.37-0.31 (m, 4H).

[0155] Examples 12-21 were synthesized according to the synthesis methods in Examples 1 and 11 of this invention. Structures and characterization data of Examples 12-21 are shown in the following table: Series number and sample structure MS m / z (ESI) 1H RMN α . δ ιΐ θ ν 12 'ό 602.3 [M+1] 1H NMR (400 MHz, DMSO-de) δ 11.44 (s, 1H), 10.18 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 3.17 (t, J = 8.7 Hz, 2H), 3.15-3.0 (m, 4H), 2.85-2.70 (m, 1H), 2.45-2.32 (m, 2H), 2.30-2.10 (m, 2H), 2.0-1.8 (m, 2H), 1.70-1.50 (m, 6H), 1.1-0.9 (m, 4H), 0.37-0.31 (m, 4H). Petition 870250081292, dated 10 / 09 / 2025, pág. 68 / 258 55 / 79 Número de série e estrutura de exemplo MS m / z (ESI) 1H RMN <91 p |i ° N F H 0 13 577,3 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,58 (s, 1H), 7,80 (d, J = 8,5 Hz, 1H), 7,16 (dd, J = 6,9, 1,9 Hz, 2H), 7,03 (dd, J = 8,6, 2,0 Hz, 1H), 6,85 (d, J = 1,9 Hz, 1H), 5,97 (s, 2H), 3,20-3,15 (m, 4H), 3,0-2,88 (m, 5H), 2,18-2,0 (m, 5H), 1,60-1,47 (m, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,37-0,31 (m, 4H). Q? (3 ο V h UMr F Η O 14 591,3 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,55 (s, 1H), 10,15 (s, 1H), 7,83 (d, J = 8,5 Hz, 1H), 7,18 (d, J = 2,2 Hz, 1H), 7,11 (d, J = 2,3 Hz, 1H), 7,05 (dd, J = 8,5, 2,1 Hz, 1H), 6,92 (d, J = 2,5 Hz, 1H), 4,3-4,2 (m, 4H), 3,19 (q, J = 7,3 Hz, 2H), 3,15-3,08 (m, 4H), 3,0-2,92 (m, 4H), 2,2-2,0 (m, 4H), 1,68-1,47 (m, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,37-0,31 (m, 4H). 9.· * F H O 15 589,3 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,49 (s, 1H), 10,14 (s, 1H), 7,83 (d, J = 8,5 Hz, 1H), 7,29 (d, J = 2,3 Hz, 1H), 7,18 (d, J = 2,1 Hz, 1H), 7,13 - 7,01 (m, 2H), 4,20 - 4,12 (m, 2H), 3,19 (q, J = 7,3 Hz, 2H), 3,15-3,05 (m, 4H), 3,0-2,93 (m, 4H), 2,74 (t, J = 6,5 Hz, 2H), 2,18-2,0 (m, 4H), 1,98-1,87 (m, 2H), 1,59 - 1,52. Petição 870250081292, de 10 / 09 / 2025, pág. 69 / 258 56 / 79 Número de série e estrutura de exemplo MS m / z (ESI) 1H RMN (m, 4H), 1,20 (t, J = 7,3 Hz, 3H), 0,370,31 (m, 4H). oU f£j F H ° 16 587,3 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,97 (s, 1H), 10,13 (s, 1H), 8,05 (s, 1H), 7,97 (s, 1H), 7,88 (d, J = 8,5 Hz, 1H), 7,19 (d, J = 2,1 Hz, 1H), 7,07 (dd, J = 8,5, 2,1 Hz, 1H), 6,57 - 6,53 (m, 1H), 3,95 (s, 3H), 3,43 (t, J = 5,8 Hz, 4H), 3,21 (q, J = 7,3 Hz, 2H), 2,98 (t, J = 5,3 Hz, 4H), 2,27-2,12 (m, 4H), 1,59 (s, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,35 (s, 4H). H oõ i 1 θ NH UÇr- F Η O 17 586,9 [M+1] NA δ I δ 0 N N '' F H 0 18 587,3 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,74 (s, 1H), 10,13 (s, 1H), 8,23 (s, 1H), 7,95 (d, J = 1,5 Hz, 1H), 7,87 (d, J = 8,5 Hz, 1H), 7,19 (d, J = 2,1 Hz, 1H), 7,06 (dd, J = 8,5, 2,1 Hz, 1H), 6,63 (d, J = 1,7 Hz, 1H), 4,13 (s, 3H), 3,73 - 3,65 (m, 4H), 3,20 (q, J = 7,3 Hz, 2H), 2,98 Petição 870250081292, de 10 / 09 / 2025, pág. 70 / 258 57 / 79 Serial number and structure of example MS m / z (ESI) 1H NMR (t, J = 5.2 Hz, 4H), 2.21-2.10 (m, 4H), 1.59 (t, J = 5.1 Hz, 4H), 1.21 (t, J = 7.4 Hz, 3H), 0.36 (s, 4H). IZ <e \ IZx ,O 586,9 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 11,72 (s, 1H), 10,15 (s, 1H), 8,10 (d, J = 1,6 Hz, 1H), 8,01 (s, 1H), 7,85 (d, J = 8,5 Hz, 1H), 7,29 (d, J = 1,7 Hz, 1H), 7,19 (d, J = 2,1 Hz, 1H), 7,06 (dd, J = 8,5, 2,1 Hz, 1H), 5,09 (s, 4H), 4,28 (s, 3H), 3,19 (t, J = 7,3 Hz, 2H), 2,99 (t, J = 5,3 Hz, 4H), 2,34-2,12 (m, 4H), 1,65-1,47 (m, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,35 (s, 4H). , C Y1......... / Μ \\ F H 0 20 572,9 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 12,92 (s, 1H), 11,93 (s, 1H), 10,16 (s, 1H), 8,07 (s, 1H), 7,94 (s, 1H), 7,87 (d, J = 8,4 Hz, 1H), 7,19 (d, J = 2,1 Hz, 1H), 7,06 (dd, J = 8,4, 2,0 Hz, 1H), 6,59 (s, 1H), 3,42 (t, J = 5,5 Hz, 4H), 3,20 (q, J = 7,3 Hz, 2H), 2,98 (t, J = 5,2 Hz, 4H), 2,27 - 2,13 (m, 4H), 1,59 (s, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,35 (s, 4H). Petition 870250081292, dated 10 / 09 / 2025, page 71 / 258 58 / 79 Serial number and example structure MS m / z (ESI) 1H NMR hn λ L 2 í 11 0 N -p...... FH ° 21 572.9 [M+1] NA Example 22 N-(7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide 22nd first stage 22b fourth stage third stage First step methyl 3-Amino-5-bromo-4-hydroxybenzoate

[0156] At room temperature, methyl 3-bromo-4-hydroxy-5-nitrobenzoate 22a (1.0 g, 3.62 mmol, commercially available) was dissolved in N,N-dimethylformamide (5 ml), and stannous chloride (2.40 g, 12.68 mmol) was added, and the mixture was purged with argon 3 times, and stirred at room temperature for 3 hours, and the mass spectrum showed that the reaction was complete. Water Petition 870250081292, dated 10 / 09 / 2025, page 72 / 258 59 / 79 (30 ml) was added and extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 3-amino-5-bromo-4-hydroxybenzoate 22b (0.85 g), with a yield of 95.36%.

[0157] MS m / z (ESI): 246.0 [M+1]. Second stage 7-Bromo-2-methylbenzo[d]oxazole-5-carboxylate methyl

[0158] At room temperature, methyl 3-amino-5-bromo-4-hydroxybenzoate 22b (850 mg, 3.45 mmol) was dissolved in 1,1,1-triethoxyethaneethane (8.85 g, 54.55 mmol, 10 ml), and 4-methylbenzenesulfonic acid (59.49 mg, 345.45 μmol) was added, and the mixture was purged with argon 3 times, heated to 80 °C and stirred for 1 hour, and the mass spectrum showed that the reaction was complete. The reaction solution was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 7-bromo2-methylbenzo[d]oxazol-5-carboxylate 22c (0.75 g), with a yield of 80.39%.

[0159] MS m / z (ESI): 270.0 [M+1]. Third stage 7-(4,4-Difluoropiperidin-1-yl)-2-methylbenzo[d]oxazole-5-carboxylate methyl

[0160] At room temperature, 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate methyl 22c (750 mg, 2.78 mmol) and 4,4-difluoropiperidine (504.55 mg, 4.17 mmol) were dissolved in toluene (20 ml), and tri(dibenzylideneacetone)palladium (127.15 mg, 138.85 μmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (172.91 mg, 277.70 μmol) and cesium carbonate (2.71 g, 8.33 mmol) were added, and the mixture was purged. with argon, heated to 100 °C and stirred for 18 hours, and the mass spectrum showed that the reaction was complete. Water (20 ml) was added, and the resulting mixture was stirred to form layers and extracted with ethyl acetate (30 ml*2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and Petition 870250081292, dated 10 / 09 / 2025, page 73 / 258 60 / 79 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 7-(4,4-difluoropiperidin-1yl)-2-methylbenzo[d]oxazol-5-carboxylate 22d (0.65 g), with a yield of 75.43%.

[0161] MS m / z (ESI): 311.1 [M+1]. Fourth stage 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazole-5-carboxylic acid

[0162] At room temperature, 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazole-5-carboxylate 22d (600 mg, 1.93 mmol) was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml), lithium hydroxide solution (2 M, 4.83 ml) was added, and the resulting mixture was stirred at room temperature for 4 hours, and the mass spectrum showed that the reaction was complete. The reaction mixture was concentrated, then water (20 ml) was added, a pH value was adjusted to 3-4 with a hydrochloric acid solution (1 M), and the resulting mixture was extracted with ethyl acetate (30 ml*3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-carboxylic acid 22e (0.53 g), with a yield of 92.52%.

[0163] MS m / z (ESI): 297.1 [M+1]. Fifth step (7-(4,4-Difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)carbamate tert-butyl

[0164] At room temperature, 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-carboxylic acid 22e (200 mg, 675.06 μmol) was dissolved in tetrahydrofuran (10 ml), triethylamine (102.46 mg, 1.01 mmol) and diphenylphosphoryl azide (278.67 mg, 1.01 mmol) were added and stirred at room temperature for 3 hours, and the mass spectrum showed that the reaction was complete. Tert-butanol (50 ml) was added to the reaction mixture, the resulting mixture was heated to 80 °C and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure until dry. The residue was purified by Petition 870250081292, dated 10 / 09 / 2025, page 74 / 258 61 / 79 silica gel column chromatography (eluent: system A) to obtain tert-butyl (7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)carbamate 22f (100 mg), with a yield of 40.32%.

[0165] MS m / z (ESI): 368.1 [M+1]. Sixth stage 7-(4,4-Difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-amine

[0166] At room temperature, tert-butyl (7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)carbamate 22f (90 mg, 244.97 μmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (55.86 mg, 489.94 μmol, 5 ml) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour, and the mass spectrum showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure until dryness and water (10 ml) was added, a pH value was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 ml*3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-amine 22g (50 mg), with a yield of 76.37%.

[0167] MS m / z (ESI): 268.1 [M+1]. Seventh stage N-(7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)-4-(ethylsulfonamido)-2(6-azaspiro[2.5]octan-6-yl)benzamide

[0168] At room temperature, 4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzoic acid 3a (50 mg, 147.74 μmol) was dissolved in acetonitrile (5 ml), 1-methylimidazole (36.39 mg, 443.23 μmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (124.36 mg, 443.23 μmol) were added, and stirred at room temperature for 1 hour. 7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-amine 22 g (51.33 mg, 192.07 μmol) was added, the mixture was heated to 60 °C and stirred for 1 hour, and the mass spectrum showed that the reaction was complete. The reaction mixture Petition 870250081292, dated 10 / 09 / 2025, page 75 / 258 62 / 79 was concentrated under reduced pressure to dryness, ethyl acetate (30 ml) was added, the resulting mixture was washed with saturated sodium bicarbonate solution (10 ml x 2) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a preparative liquid phase (AKZONOBEL Kromasil separatory column; 250 x 21.2 mm ID; 5 µm, 20 ml / min; mobile phase A: 0.05% NH4CO3 + H2O, mobile phase B: CH3CN), and freeze-dried to obtain N-(7-(4,4-difluoropiperidin-1-yl)-2-methylbenzo[d]oxazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22 (5.7 mg), with a yield of 5.2%.

[0169] MS m / z (ESI): 588.3 [M+1].

[0170] 1H RMN (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 10.15 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.18 (s, 2H), 7.04 (dd, J = 8.5, 2.1 Hz, 1H), 3.49 (t, J = 5.7 Hz, 4H), 3.20 (q, J = 7.3 Hz, 2H), 3.04-2.92 (m, 4H), 2.60 (s, 3H), 2.22 - 2.10 (m, 4H), 1.66-1.43 (m, 4H), 1,21 (t, J = 7.3 Hz, 3H), 0.35 (s, 4H). Example 23 N-(7-(4,4-difluoropiperidin-1-il)-1-oxoisoindolin-5-il)-4-(etilsulfonamido)-2-(6azaspiro[2.5]octan-6-il)benzamida ΡΜΒλΡΜΒχ Petition: 870250081292, on September 10, 2025, page. 76 / 258 63 / 79 First step 5-Bromo-7-fluoro-2-(4-methoxybenzyl)isoindolin-1-one

[0171] At room temperature, methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate 2c (1.0 g, 3.07 mmol) and (4-methoxyphenyl)methylamine (631.27 mg, 4.60 mmol) were dissolved in N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine (793.00 mg, 6.14 mmol) was added, the resulting mixture was heated to 40 °C and stirred for 10 hours, and the mass spectrum showed that the reaction was complete. Water (30 ml) was added to the reaction mixture and the resulting mixture was extracted with dichloromethane (50 ml*2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo7-fluoro-2-(4-methoxybenzyl)isoindolin-1-one 23a (0.79 g), with a yield of 73.53%.

[0172] MS m / z (ESI): 349.8 [M+1]. Second stage 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-(4-methoxybenzyl)isoindolin-1-one

[0173] At room temperature, 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindolin-1-one 23a (450 mg, 1.29 mmol) and 4,4-difluoropiperidine (233.48 mg, 1.93 mmol) were dissolved in dimethyl sulfoxide (10 ml), N,N-diisopropylethylamine (332.17 mg, 2.57 mmol) was added, the resulting mixture was heated to 150 °C and stirred for 6 hours, and the mass spectrum showed that the reaction was complete. Water (20 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (30 ml*2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-(4,4-difluoropiperidin-1-yl)-2-(4-methoxybenzyl)isoindolin-1-one 23b (0.44 g), with a yield of 75.8%.

[0174] MS m / z (ESI): 450.8 [M+1]. Petition 870250081292, dated 10 / 09 / 2025, page 77 / 258 64 / 79 Third step (tert-butyl 7-(4,4-Difluoropiperidin-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate

[0175] At room temperature, 5-bromo-7-(4,4-difluoropiperidin-1-yl)-2-(4-methoxybenzyl)isoindolin-1-one 23b (400 mg, 886.32 μmol) and tert-butyl carbamate (207.66 mg, 1.77 mmol) were dissolved in 1,4-dioxane (10 mL), and palladium acetate (19.90 mg, 88.63 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (102.57 mg, 177.26 μmol) and cesium carbonate (866.34 mg, 2.66 mmol) were added, and the mixture was purged with argon, heated to 100 °C and stirred for 18 hours, and the mass spectrum showed that the reaction was complete. Water (20 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (30 ml*2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl (7-(4,4-difluoropiperidin-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate 23c (0.4 g), with a yield of 92.57%.

[0176] MS m / z (ESI): 488.0 [M+1]. Fourth step 5-amino-7-(4,4-difluoropiperidin-1 -yl)isoindolin-1 -one

[0177] At room temperature, tert-butyl 23c (7-(4,4-difluoropiperidin-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate (400 mg, 820.45 μmol) was dissolved in trifluoroacetic acid (4 ml) and stirred at room temperature for 18 hours. Methanesulfonic acid (2 ml) was added, the mixture was heated to 60 °C and stirred for 3 hours, and the mass spectrum showed that the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated to dryness. Water (20 ml) was added to the residue, a pH value was adjusted to 8-9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 ml*3). The combined organic phase was washed with saturated sodium chloride solution and dried over sulfate. Petition 870250081292, dated 10 / 09 / 2025, page 78 / 258 65 / 79 anhydrous sodium, filtered and concentrated under reduced pressure to obtain 5-amino7-(4,4-difluoropiperidin-1-yl)isoindolin-1-one 23d (0.2 g), with a yield of 91.21%.

[0178] MS m / z (ESI): 268.1 [M+1]. Fifth stage N-(7-(4,4-difluoropiperidin-1-yl)-1-oxoisoindolin-5-yl)-4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide

[0179] At room temperature, 4-(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzoic acid 3a (150 mg, 443.23 μmol) was dissolved in acetonitrile (10 ml), 1-methylimidazole (110.51 mg, 1.33 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (373.09 mg, 1.33 mmol) were added, and the resulting mixture was stirred at room temperature for 1 hour. 5-amino-7-(4,4-difluoropiperidin-1-yl)isoindolin-1-one 23d (130.31 mg, 487.56 μmol) was added, the mixture was heated to 60 °C and stirred for 2 hours, and the mass spectrum showed that the reaction was completed. The reaction solution was purified by a preparative liquid phase (AKZONOBEL Kromasil separatory column; 250x21.2 mm ID; 5 μm, 20 ml / min; mobile phase A: 0.05% NH4CO3+H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidin-1-yl)-1-oxoisoindolin-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6yl)benzamide 23 (43.0 mg), with a yield of 15.75%.

[0180] MS m / z (ESI): 588.3 [M+1].

[0181] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.82 (s, 1H), 8.18 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.08 (s, 1H), 7.05 (dd, J = 8.5, 2.1 Hz, 1H), 4.28 (s, 2H), 3.44-3.22 (m, 4H), 3.20 (q, J = 7.3 Hz, 2H), 2.97 (t, J = 5.2 Hz, 4H), 2.23-2.09 (m, 4H), 1.61 - 1.50 (m, 4H), 1.21 (t, J = 7.3 Hz, 3H), 0.35 (s, 4H).

[0182] Examples 24-26 were synthesized according to the synthesis methods in Examples 1 and 11 of this invention. Structures and characterization data of Examples 24-26 are shown in the following table: Petition 870250081292, dated 10 / 09 / 2025, p. 79 / 258 66 / 79 Número de série e estrutura de exemplo MS m / z (ESI) 1H RMN 0,^ F N 'g 24 H ° 558,8 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,61 (s, 1H), 10,13 (s, 1H), 8,20 (s, 1H), 7,85 (d, J = 8,5 Hz, 1H), 7,72 (d, J = 1,6 Hz, 1H), 7,18 (d, J = 2,2 Hz, 1H), 7,05 (dd, J = 8,5, 2,1 Hz, 1H), 6,35 (d, J = 1,7 Hz, 1H), 4,50 (t, J = 12,2 Hz, 4H), 4,11 (s, 3H), 3,20 (s, 2H), 2,98 (t, J = 5,2 Hz, 4H), 1,65-1,49 (m, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,36 (s, 4H). Co 'tf)' °' O=\ »n \ CM ZI rv) \ 572,9 [M+1] 1H RMN (400 MHz, DMSO-de) δ 11,74 (s, 1H), 10,15 (s, 1H), 8,19 (s, 1H), 7,89 (d, J = 8,6 Hz, 1H), 7,77 (s, 1H), 7,21 (d, J = 2,1 Hz, 1H), 7,07 (dd, J = 8,6, 2,1 Hz, 1H), 6,26 (s, 1H), 4,19-4,13 (m, 2H), 4,12 (s, 3H), 3,80 (t, J = 7,2 Hz, 2H), 3,20 (q, J = 7,3 Hz, 2H), 2,99 (t, J = 5,3 Hz, 4H), 2,61 - 2,55 (m, 2H), 1,62 (d, J = 6,0 Hz, 4H), 1,21 (t, J = 7,3 Hz, 3H), 0,37 (s, 4H).i ii 0 NF Η 0 26 598.9 [M+1] 1H NMR (400 MHz, DMSO-de) δ 11.83 (s, 1H), 10.09 (s, 1H), 8.23 ​​(s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.5, 2.1 Hz, 1H), 6.63 (d, J = 1.7 Hz, 1H), 4.13 (s, 3H), 3.69 (t, J = 5.7 Hz, 4H), 2.98 (t, J = 5.2 Hz, 4H), 2.78-2.71. Petition 870250081292, dated 10 / 09 / 2025, p. 80 / 258 67 / 79 Serial number and example structure MS m / z (ESI) 1H NMR (m, 1H), 2.22-2.11 (m, 4H), 1.66-1.53 ​​(m, 4H), 1.03 - 0.97 (m, 4H), 0.36 (s, 4H).

[0183] Examples 27-28 were synthesized according to the synthesis method in Example 2 of the present invention. Structures and characterization data of Examples 27-28 are shown in the following table: Número de série e estrutura de exemplo MS m / z (ESI) 1H RMN ( / ° '—z W / \__ / Z ZZ q Vo 12 ,o ,ω' V 567,9 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 12,08 (s, 1H), 10,03 (s, 1H), 7,82 (d, J = 8,5 Hz, 1H), 7,72 (s, 1H), 7,14 (s, 1H), 7,06 (s, 1H), 7,01 (d, J = 8,6 Hz, 1H), 4,37 (s, 2H), 3,82 - 3,74 (m, 4H), 3,25-3,19 (m, 4H), 3,17-3,12 (m, 2H), 2,99 (s, 3H), 2,98-2,92 (m, 4H), 1,57 (s, 4H), 1,20 (t, J = 7,3 Hz, 3H), 0,36 (s, 4H). v ri ° N N 0 fAj h ΙΛνΛ7-0Η F H O 28 617,9 [M+1] 1H RMN (400 MHz, DMSO-d6) δ 11,91 (s, 1H), 10,11 (s, 1H), 7,82 (d, J = 8,5 Hz, 1H), 7,74 (s, 1H), 7,21 - 7,09 (m, 2H), 7,03 (dd, J = 8,6, 2,0 Hz, 1H), 4,95 (s, 1H), 4,37 (s, 2H), 3,76 (t, J = 6,5 Hz, 2H), 3,38-3,32 (m, 4H), 3,323,31 (m, 2H), 3,00 (s, 3H), 2,97 (t, J = Petição 870250081292, de 10 / 09 / 2025, pág. 81 / 258 68 / 79 5,2 Hz, 4H), 2,23 - 2,10 (m, 4H), 1,55 (t, J = 5,4 Hz, 4H), 0,35 (s, 4H).

[0184] O Exemplo 29 foi sintetizado de acordo com o método de síntese no Example 1 of the present invention. The structure and characterization data of Examples 29 are shown in the following table: Serial number and example structure MS m / z (ESI) 1H MRN IO .O °' 'ZI / σ> O=( cn ZT ry) •q. 591.3 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 10.06 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.12 - 6.96 (m, 2H), 4.95 (t, J = 5.6 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 3.75 (q, J = 6.3 Hz, 2H), 3.3 - 3.2 (m, 2H), 3.27-3.12 (m, 6H), 3.0-2.9 (m, 4H), 2.15-2.0 (m, 4H), 1.65-1.46 (m, 4H), 0.37-0.31 (m, 4H). Biological assessment Example Test 1. Determination of inhibition of the compounds of the present invention on OVCAR-3 cell proliferation.

[0185] The influences of the compounds of the present invention on OVCAR-3 cell proliferation were determined by the following method. OVCAR-3 cells (containing the TP53 R248Q mutation) were acquired from the Cell Bank of the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and cultured in RPMI 1640 culture medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / ml streptomycin. Cell viability was determined using a CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, article number Petition 870250081292, dated 10 / 09 / 2025, page 82 / 258 69 / 79 G7573).

[0186] An experimental method was operated according to the steps in the kit instruction, which was briefly described as follows: a test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then the stock solution was diluted with the above RPMI 1640 culture medium to prepare a test sample, and a final concentration of the compound was in a range of 1000 nM–0.015 nM. Cells in a logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, cultured in a 5% CO2 incubator at 37 °C overnight, and then the test compound was added to the culture continuously for 72 hours.After the culture was complete, 50 μl of CellTiter-Glo detection solution was added to each well, the plates were shaken for 5 minutes and then left to stand for 10 minutes, and subsequently, a luminescence value from each sample well was read by a microplate reader in Luminescence mode. By comparison with a numerical value from a control group (0.3% DMSO), a percentage inhibition rate of the compound at each concentration was calculated, and then non-linear regression analysis was performed based on the logarithm of the concentration-inhibition rate of the compound in GraphPad Prism 5 software, in order to obtain an IC50 value of the compound's inhibition on cell proliferation, which are shown in Table 1. Table 1. IC50 data of the compounds of the present invention demonstrating inhibition of OVCAR-3 cell proliferation. Example serial number IC50 (nM) Example serial number IC50 (nM) Example serial number IC50 (nM) AMG 650 control composite 64.5 14 8.4 22 33.2 1 0.75 15 18.4 23 3.6 2 4.3 16 36.7 24 13.4 Petition 870250081292, dated 10 / 09 / 2025, page 83 / 258 70 / 79 3 11.2 17 6.6 25 33.6 6 9.1 18 3.3 27 1.96 7 11 20 20.3 28 6.8 13 5.5 21 16.6

[0187] Conclusion: the compounds of the present invention have a relatively good inhibitory effect on OVCAR-3 cell proliferation IC50<50 nM

[0188] Note: the structure of the AMG 650 (prepared according to Example 4 of published patent WO2020132648A1) was as follows: Example Test 2. Determination of inhibition of the compounds of the present invention on HT-29 cell proliferation.

[0189] The influences of the compounds of the present invention on HT-29 cell proliferation were determined by the following method. HT-29 cells (containing the TP53 R273H mutation) were acquired from the Cell Bank of the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and cultured in McCOY 5A culture medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / ml streptomycin. Cell viability was determined using a CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, article number G7573).

[0190] An experimental method was operated according to the steps in the kit instruction, which was briefly described as follows: a test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then the stock solution was diluted with McCOY's 5A culture medium above to prepare a test sample, and a final concentration of Petition 870250081292, dated 10 / 09 / 2025, p. 84 / 258 The 71 / 79 compound was in a range of 1000 nM–0.015 nM. Cells in a logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, cultured in a 5% CO2 incubator at 37 °C overnight, and then the test compound was added to the culture continuously for 120 hours. After the culture was complete, 50 μl of CellTiter-Glo detection solution were added to each well, the plates were shaken for 5 minutes and then left to stand for 10 minutes, and subsequently, a luminescence value from each sample well was read by a microplate reader in Luminescence mode.By comparing the compound's percentage inhibition rate to a numerical value from a control group (DMSO at 0.3%), a percentage inhibition rate of the compound at each concentration was calculated. Then, non-linear regression analysis was performed based on the concentration-inhibition rate logarithm of the compound using GraphPad Prism 5 software, in order to obtain an IC50 value for the compound's inhibition of cell proliferation, which are shown in Table 2. Table 2. IC50 data of the compounds of the present invention demonstrating inhibition of HT-29 cell proliferation. Example serial number IC50 (nM) Example serial number IC50 (nM) Example serial number IC50 (nM) AMG 650 control composite 61.7 14 9.2 28 18.9 1 2.4 15 23.6 2 3.9 16 35.7 3 6.6 18 7.7 6 10.7 21 13.8 7 7.8 23 5.8 13 7.3 24 4.1

[0191] Conclusion: the compounds of the present invention have an inhibitory effect Petition 870250081292, dated 10 / 09 / 2025, page 85 / 258 72 / 79 relatively good at HT-29 cell proliferation, IC50 <50 nM. Example Test 3. Inhibition test of the compounds of the present invention on the enzymatic activity of KIF18A.

[0192] The degrees of inhibition of the compounds of the present invention on the enzymatic activity of recombinant human KIF18A in vitro were determined by the following method. An ADP-Glo™ Kinase Assay kit (article number V9102) from Promega Company was used in this method. The detailed experimental operation can be referred to in the kit instructions.

[0193] An experimental flow was briefly described as follows: a test compound was first dissolved in DMSO to prepare a stock solution, then the stock solution was gradient-diluted with reaction buffer A (15 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% Pluronic F-68), and a final concentration of the test compound in the reaction system was in the range of 10000 nM–0.15 nM; and a KIF18A protein and ATP working solution was prepared using reaction buffer B (15 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% Pluronic F-68, 37.5 μg / ml tubulin, 1.25 μM paclitaxel). The reaction was run in a 384-well microplate.The test compound and recombinant human KIF18A protein (final concentration of 100 nM, provided by GenScript for expression) were added to the wells and incubated at room temperature for 20 minutes. Subsequently, ATP solution (component V915A of the ADP-Glo® Kinase Assay kit, final concentration of 60 μM) was added to the reaction solution, and the resulting system was incubated at room temperature for 20 minutes. Then, 5 μl of ADP-Glo ​​Reagent was added to the reaction system, and the resulting system was incubated at room temperature for 50 minutes. Finally, 10 μl of Kinase Detection Reagent was added to the reaction system, and the resulting system was incubated at room temperature for 30 minutes. After incubation was complete, a chemiluminescence intensity value for each well was determined using a microplate reader in Luminescence mode. comparison with an intensity value. Petition 870250081292, dated 10 / 09 / 2025, page 86 / 258 73 / 79 light-based control group (DMSO at 0.1%), a percentage inhibition rate of the compound at each concentration was calculated, and nonlinear regression analysis was performed based on the concentration-inhibition rate logarithm value of the compound in GraphPad Prism 5 software, in order to obtain an IC50 value for the compound, which are shown in Table 3. Table 3. IC50 data of the compounds of the present invention demonstrating inhibition of KIF18A enzymatic activity. Example Serial Number IC50 (nM) Example Serial Number IC50 (nM) Example Serial Number IC50 (nM) AMG 650 Control Composite 173 11 263 24 85.7 1 52 12 173 25 198 2 142 13 291 26 256 3 72.5 14 184 27 109 4 212 16 209 28 142 5 134.3 17 280 29 316 6 60.9 20 197 7 157 21 229 8 90.6 22 98.5 10 267 23 123

[0194] Conclusion: the compounds of the present invention have a significant inhibitory effect on KIF18A enzymatic activity, IC50<500 nM. Example of Test 4. Pharmacokinetic testing of the compounds of the present invention in mice. 1. Experimental purpose

[0195] ICR mice were adopted as test animals, and administered intragastrically with a control compound AMG650 and Petition 870250081292, dated 10 / 09 / 2025, page 87 / 258 74 / 79 compounds 1, 18 and 29 of the present invention, and then drug concentrations in plasma at different times were determined by an LC / MS / MS method, in order to study pharmacokinetic characteristics of the compounds of the present invention in mice. 2. Experimental design 2.1 Experimental drugs and animals

[0196] AMG650 control compound and Compounds 1, 18 and 29. ICR mice, males, 27.3-30.3 g, acquired from Vital River Laboratory Animal Technology Co., Ltd. 2.2 Drug preparation

[0197] An appropriate amount of compound to be tested was weighed, appropriate amounts of DMA (N,N-dimethylacetamide), CrEL (polyoxyethylene castor oil 35) and 5% GS (5% glucose injection) were added sequentially, and the resulting system was uniformly mixed by ultrasonic vortexing to prepare a 1 mg / ml preparation, wherein DMA, CrEL and 5% GS = 10:10:80 (v:v:v). 2.3 Administration

[0198] ICR mice in each compound injection group to be tested (9 mice in each group) were fasted overnight and then administered intragastrically with the compound (PO, a compound administration dosage was 10 mg / kg and a compound administration volume was 10 ml / kg), and were fed 4 hours after administration. 3. Operation

[0199] 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, and 24 hours before and after administration, approximately 0.1 μl of blood was collected via orbit, and a complete blood sample was placed in an anticoagulation tube containing EDTA-K2. The collected blood sample was placed on ice, and the plasma was centrifugally separated (centrifugation conditions: 1500 g, 10 minutes). The collected plasma was stored at -40 ~ -20 °C before analysis. Petition 870250081292, dated 10 / 09 / 2025, page 88 / 258 75 / 79

[0200] The concentration of the compound to be tested in the plasma of mice after intragastric administration was determined by LC-MS / MS. 4. Results of pharmacokinetic parameters

[0201] The pharmacokinetic parameters of the compounds to be tested are shown in Table 4 below. Table 4 Pharmacokinetic parameters of compounds to be tested in mice Serial number of compound Pharmacokinetic experiment Route of administration (Dosage) Plasma concentration Cmax (ng / ml) Area under the curve AUC0- (ng^h / ml) Half-life period T1 / 2 (h) Control compound AMG650 Oral administration (10 mg / ml) 3050 52500 9.64 Example 1 Oral administration (10 mg / ml) 12417 95245 7.36 Example 18 Oral administration (10 mg / ml) 3030 45900 5.2 Example 29 Oral administration (10 mg / ml) 6960 25881 1.24

[0202] Conclusion: compounds 1, 18 and 29 of the present invention have both a high plasma concentration and a large area under the curve, and have good pharmacokinetic properties. Example of Test 5. Pharmacodynamic testing of Compound 1 of the present invention in mice. 1. Experimental purpose Petition 870250081292, dated 10 / 09 / 2025, page 89 / 258 76 / 79

[0203] An antitumor effect of Compound 1 of the present invention in a BALB / c nude mouse animal model with subcutaneous xenograft of human ovarian adenocarcinoma tumor fragment OVCAR-3 was evaluated. 2. Experimental animals

[0204] Naked BALB / c mice, females, 6-7 weeks old, acquired from Jiangsu Gempharmatech Biotechnology Co., Ltd. 3. Preparation of test compounds

[0205] Mice in a solvent control group were given DMA: CrEL: GS at 5%=10: 10: 80 (v: v: v).

[0206] AMG650: an appropriate amount of AMG-650 was weighed, appropriate amounts of DMA, CrEL and 5% GS were added sequentially, and the resulting system was uniformly mixed by ultrasonic vortex to prepare preparations of 0.8 mg / ml and 0.4 mg / ml respectively, wherein DMA, CrEL and 5% GS = 10:10:80 (v:v:v).

[0207] Compound 1: an appropriate amount of Compound 1 was weighed, appropriate amounts of DMA, CrEL and 5% GS were added sequentially, and the resulting system was uniformly mixed by ultrasonic vortex to prepare preparations of 0.8 mg / ml and 0.4 mg / ml respectively, wherein DMA, CrEL and 5% GS = 10:10:80 (v:v:v). 4. Acquisition of tumor fragment for inoculation

[0208] A suitable animal bearing an OVCAR-3 tumor was selected, a 1 mm*1 mm*1 mm OVCAR-3 tumor fragment was aseptically acquired and placed in normal saline for later use, which was used for subcutaneous tumor inoculation on the right side of the back of naked BALB / c mice. 5. Inoculation and grouping of animals

[0209] A tumor fragment of OVCAR-3 of approximately 1 mm*1 mm*1 mm was inoculated subcutaneously on the right side of the backs of female naked BALB / c mice. When an average tumor volume reached approximately 100-250 mm3, the mice were randomly grouped according to the Petition 870250081292, dated 10 / 09 / 2025, p. 90 / 258 77 / 79 tumor size, with 6 mice in each group. 6. Administration and observation of animals

[0210] The animals in each group were given the test compound once a day according to an animal weight at a fixed time each day by oral administration (po), the animals started being administered the test compound for the first time on the grouping day for 22 consecutive days, and the animal weight was recorded every day.

[0211] The 1st group (G1) was a solvent control group;

[0212] The 2nd group (G2) and the 3rd group (G3) were orally administered AMG-650 at dosages of 8 mg / kg and 4 mg / kg respectively once daily (QD); and

[0213] Group 4 (G4) and Group 5 (G5) were orally administered Compound 1 at dosages of 8 mg / kg and 4 mg / kg respectively once daily (QD).

[0214] Tumor formation at an inoculation site in animals from each group was observed, and tumor volume was measured twice weekly and calculated according to the following formula: A tumor volume (TV), a relative tumor volume (RTV), a relative tumor proliferation ratio (T / C), and a relative tumor inhibition ratio (TGI) were calculated according to the following formulas: (1) TV (tumor volume) = 1 / 2xaxb2, where a and b represent respectively a tumor length and a tumor width; (2) RTV (relative tumor volume) = Vt / Vo, where Vo was a tumor volume measured at pooling time, and Vt was a tumor volume at each measurement; (3) T / C (%) = Trtv / Crtv x 100%, where Trtv was RTV of a treatment group, and Crtv was RTV of a solvent control group; and (4) TGI% = (1 - T / C) x 100%, where T and C were relative tumor volumes of the treatment group and the solvent control group at a specific time point, respectively. 7. Results Petition 870250081292, dated 10 / 09 / 2025, page 91 / 258 78 / 79 Table 5. Efficacy analysis of test compounds across dose groups in an OVCAR-3 human ovarian adenocarcinoma tumor fragment xenograft model. Group 16 days after administration Tumor volume (x±S) Relative tumor volume (x±S) % of GI tract 1st group Control Solvent control 620±80 3.27±0.28 - 2nd group AMG650 (8 mg / kg) 243±35 1.29±0.16 60.5% 3rd group AMG650 (4 mg / kg) 511±49 2.77±0.26 15.3% 4th group Compound 1 (8 mg / kg) 31±8 0.16±0.03 95.2% 5th group Compound 1 (4 mg / kg) 120±27 0.61±0.11 81.3%

[0215] Note: the data were expressed as “mean value ± standard error”.

[0216] Conclusion: Under the experimental conditions specified in this study, Compound 1 of the present invention demonstrated significantly enhanced inhibition of tumor growth at both 8 mg / kg and 4 mg / kg doses compared to the solvent control and AMG650 in a BALB / c nude mouse model bearing subcutaneous xenografts of human ovarian adenocarcinoma tumor fragment from OVCAR-3.

[0217] Unless otherwise defined, all terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0218] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of Petition 870250081292, dated 10 / 09 / 2025, p. 92 / 258 79 / 79 present invention, and those skilled in the art may carry out various other substitutions, alterations and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but only defined by the claims. Petition 870250081292, dated 10 / 09 / 2025, p. 93 / 258

Claims

1 / 12 CLAIMS 1. Compound as shown by general formula (I), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof: G (I) characterized in that: ring A is selected from 5-7 membered heterocyclyl or 5-7 membered heteroaryl; G is selected from “Ή or -¼ ; Xi and X2 are each independently selected from CRa or an N atom; Yi, Y2 and Y3 are each independently selected from CRb or an N atom, and at most two of Yi, Y2 and Y3 are N atoms at the same time; Ra and R6 are each independently selected from a hydrogen, halogen, hydroxyl, cyano, alkyl or alkoxy atom, wherein the alkyl or alkoxy is optionally further replaced by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;RA is the same or different, and is each independently selected from a hydrogen, halogen, hydroxyl, cyano, alkyl or alkoxy atom, Petition 870250081292, 10 / 09 / 2025, page 94 / 258 2 / 12 wherein alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; or, two RAs form a C(O) together with the same carbon atom to which the two RAs are attached; Li is selected from a C1-C6 alkylene bond, wherein the alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy, and one or more methylene groups of the alkylene are optionally substituted by one or more O, S(O)r, C(O) or NRc; Rc is selected from a hydrogen or alkyl atom; L2 is selected from R3 or N₂R₃;R3 is each independently selected from a hydrogen or alkyl atom, wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; and R3 is preferably a hydrogen atom; R1 is selected from a hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl or heteroaryl atom, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10;R4 is selected from cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -C(O)R5, -C(O)OR5, NHC(O)R5, -NHC(O)OR5, -NR6R7, -C(O)NR6R7, -CH2NHC(O)OR5, -CH2NR6R7 or -S(O)rR5, wherein alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further replaced by one or more Petition 870250081292, dated 10 / 09 / 2025, p. 95 / 258 3 / 12 selected substituents of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, SO2NR9R10 or -NR9C(O)R10;R5 is each independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10;R6 and R7 are each independently selected from a hydrogen, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl atom, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10 or -NR9C(O)R10;or, R6 and R7 form a 4-8 membered heterocycline together with the atoms to which R6 and R7 are attached, wherein the 4-8 membered heterocycline contains one or more N, O or S(O)r, and the 4-8 membered heterocycline is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycline, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, NR9R10, -C(O)NR9R10, -SÜ2NR9R10 or -NR9C(O)R10;R8, R9 and R10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate group; n is 0, 1, 2, 3 or 4; er is each independently 0, 1 or 2.

2. Compound, or stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, which is a compound as shown by formula (II) or (III), or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof: (ii) (iii) characterized in that the ring definitions A, Xi, X2, RA, R1, R4, Li and en are as described in claim 1.

3. A compound, or stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that: Li is selected from a C1-C6 alkylene bond, wherein the alkylene is optionally further substituted by one or more hydroxyl groups, and one or more methylene groups of the alkylene are optionally substituted by one or more O, S(O)r, C(O) or NRc; r is 2; and Rc is selected from a hydrogen or methyl atom.

4. Compound, or stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that Li is selected from a linkage, - Petition 870250081292, dated 10 / 09 / 2025, p. 97 / 258 5 / 12 NHSO2CH2CH2-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-,NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-,C(O)N(CH3)CH2CH2-, -CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2- or -CH2SO2CH2CH2-.

5. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that R1 is selected from a hydrogen, hydroxyl, alkyl, heterocyclyl, cycloalkyl, or heteroaryl atom, wherein the alkyl, heterocyclyl, cycloalkyl, or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl or alkyl.

6. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that r1 is H₂O or 7. Compound, or stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt thereof, according to claim 1 or %% ~? N 'k 2, characterized in that < 1 is H υ .

8. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that Xi and X2 are each independently selected from CH.

9. Compound, or stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that ring A is selected from: Petition 870250081292, dated 10 / 09 / 2025, page 98 / 258 6 / 12 10. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that ring A is selected from HN-N HN N< or N-NH 11. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that: RA is each independently selected from a hydrogen or methyl atom; or, two RA form a C(O) together with the same carbon atom to which the two RA are attached.

12. Compound, or stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that: R4 is each independently selected from 3-10 membered heterocyclyl or C3-C10 cycloalkyl, wherein the heterocyclyl or cycloalkyl is optionally further substituted by one or more hydroxyl groups or halogens.

13. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that: R4 is each independently selected from C2-C6 alkenyl or C1-C6 alkyl, wherein the alkenyl or alkyl is optionally further substituted by one or more hydroxyl or halogen groups.

14. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 12, characterized in that: R4 is f or F 15. Compound, or stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that R4 is or 16. A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein the compound is characterized by being: Petition 870250081292, dated 10 / 09 / 2025, p. 100 / 258 8 / 12 Petition 870250081292, dated 10 / 09 / 2025, p. 101 / 258 9 / 12 Petition 870250081292, dated 10 / 09 / 2025, p. 102 / 258 10 / 12 , , , or 17. Pharmaceutical composition, wherein the pharmaceutical composition is Petition 870250081292, dated 10 / 09 / 2025, page 103 / 258 11 / 12 characterized by comprising an effective amount of the compound, or of a stereoisomer thereof, of a tautomer thereof or of a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 16, and a pharmaceutically acceptable carrier, an excipient or a combination of the two.

18. Use of the compound, or of a stereoisomer thereof, of a tautomer thereof, or of a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16, or of the pharmaceutical composition as defined in claim 17, characterized in that it is in the preparation of a KIF18A inhibitor.

19. Use of the compound, or of a stereoisomer thereof, of a tautomer thereof or of a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 16, or of the pharmaceutical composition as defined in claim 17, characterized in that it is in the preparation of a medicament for treating a KIF18A-mediated disease, wherein the KIF18A-mediated disease is preferably cancer.

20. Use according to claim 19, characterized in that the cancer is selected from a hepatocellular carcinoma, a glioblastoma, a colon cancer, a breast cancer, a lung cancer, a cholangiocarcinoma, a pancreatic cancer, a prostate cancer, a bladder cancer, a head cancer, a neck cancer, a cervical cancer, an ovarian cancer, a synovial sarcoma, a rhabdomyosarcoma, a colorectal cancer or a pulmonary adenocarcinoma.

21. Use of the compound, or of a stereoisomer thereof, of a tautomer thereof, or of a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16, or of the pharmaceutical composition as defined in claim 17, characterized in that it is in the preparation of a medicament for treating cancer.

22. Use according to claim 21, characterized in that the cancer is selected from a hepatocellular carcinoma, a glioblastoma, a colon cancer, a breast cancer, a lung cancer, a cholangiocarcinoma, a pancreatic cancer, a prostate cancer, a bladder cancer, a head cancer, a neck cancer, a cervical cancer, an ovarian cancer, a synovial sarcoma, a rhabdomyosarcoma, a colorectal cancer, or a pulmonary adenocarcinoma.