Compound acting as a wrn helicase inhibitor

Description

1 / 114 COMPOUND ACTING AS A WRN HELICASE INHIBITOR

[0001] The present invention claims the right to the following priorities:

[0002] Order No. CN2023103018345, filing date: March 24, 2023;

[0003] Order No. CN202311004828X, filing date: August 9, 2023;

[0004] Application No. CN2023110500915, filing date: August 18, 2023;

[0005] Order No. CN2024102950619, filing date: March 14, 2024. TECHNICAL FIELD

[0006] This disclosure relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof. Specifically, this disclosure relates to a class of compounds such as WRN helicase inhibitors. FUNDAMENTALS

[0007] The entire human genome contains numerous regions of short tandem repeat sequences. These repetitive DNA regions are known as microsatellites and are prone to slippage and errors during replication, therefore highly dependent on the MMR (mismatch repair) system for repair. When the MMR (mismatch repair) system becomes dysfunctional, it leads to dMMR (deficient mismatch repair), resulting in the inability to recognize and repair microsatellite replication errors. This causes MSI (microsatellite instability), which can lead to frameshift mutations, causing abnormalities in tumor-related genes and further inducing the occurrence and development of cancer.In 2017, Immune Checkpoint Inhibitors (ICIs) were approved for the treatment of Microsatellite Instability / Deficient Mismatch Repair (MSI-H / dMMR) tumors, making MSI-H / dMMR the first pan-cancer tumor biomarker. Microsatellite instability (MSI-H) cancer cells depend on WRN helicase activity (Werner RecQ helicase syndrome). Inhibition of WRN can induce DNA double-strand breaks, activate the DNA damage response, and induce apoptosis and cell cycle arrest. Petition 870250086442, dated 09 / 24 / 2025, page 63 / 530 2 / 114 cell. Common treatment approaches for dMMR / MSI-H cancer patients include targeted therapy, chemotherapy, and immunotherapy. The clinical efficacy of targeted therapy and chemotherapy is limited by drug resistance and toxicity, and approximately half of patients receiving immunotherapy do not respond positively to immune checkpoint inhibitors. 45-60% of MSI-H cancer patients do not respond to immunotherapy, and the problems of primary and secondary resistance in targeted therapy, chemotherapy, and immunotherapy need to be urgently addressed. In 2019, Harvard's Broad Institute and MIT analyzed the Achilles and Drive databases to assess the dependence of each cell line on different targets. They found that RecQ DNA helicase WRN activity is essential both in vivo and in vitro for dMMR / MSI-H cell lines, while MSS cells do not depend on WRN for survival.In MSI-H models, WRN knockout induces double-strand DNA breaks and selectively promotes apoptosis and cell cycle arrest. This tumor suppressor mechanism differs from targeted drugs (which inhibit specific oncogenic alterations in cancer cells) and immunotherapies (which inhibit immune evasion and tolerance). In 2021, Dr. Mathew J Garnett's research group at the Wellcome Sanger Institute demonstrated, using PDX models, that WRN inhibitors could serve as second- or third-line monotherapy for patients with dMMR. In dMMR tumors, tumor mutability is negatively correlated with the response to immune checkpoint blockade, while WRN sensitivity is independent of mutational burden. Due to their different modes of action, combination therapy with checkpoint inhibitors, chemotherapy, or targeted therapy with WRN inhibitors can suppress cross-resistance and promote tumor eradication.Furthermore, since the loss of DNA repair modulates the structure of neoantigens and increases the mutational load, leading to intensified immune responses, WRN inhibition may also synergize with immunotherapy. Thus, WRN may serve as a critical target for monotherapy or combination therapy with targeted agents, chemotherapy, or immunotherapy in dMMR / MSI-H tumors.

[0008] MSI-H tumors can occur in various locations, with the highest incidence observed Petition 870250086442, dated 09 / 24 / 2025, page 64 / 530 3 / 114 in endometrial cancer (31%), colon adenocarcinoma (20%), and gastric cancer (19%). Approximately 325,000 new cases of MSI-H tumors are diagnosed annually in the United States and about 300,000 in China, indicating a substantial market value for drug development. In mismatch repair-proficient (MSS) tumors, the loss (or reduction) of WRN expression does not affect tumor cell growth. In mismatch repair-deficient (MSI-H) tumors, the simultaneous loss (or reduction) of WRN expression can lead to increased accumulation of DNA double-strand breaks in cells, cell cycle arrest in the G1 or G2 / M phase, and ultimately, tumor cell death. This is the so-called synthetic lethality effect. The development of WRN helicase inhibitors is expected to be one of the effective treatment approaches for MSI-H cancers. SUMMARY

[0009] In one aspect of the present disclosure, the present disclosure provides a compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

[0010] characterized by the fact that

[0011] Ring A is selected from the group consisting of 5- to 10-membered phenyl and heteroaryl groups, wherein the 5- to 10-membered phenyl and heteroaryl groups are optionally replaced by 1, 2 or 3 Ra;

[0012] Ring B is selected from the group consisting of 3- to 20-membered C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C4- to 20-membered C4- to 20-membered cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C6- to 20-membered aryl and heteroaryl groups;

[0013] ring C is selected from the group consisting of C6-20 aryl and heteroaryl groups with 5 to 20 members;

[0014] ring D is selected from the group consisting of C3-20 cycloalkyl, heterocycloalkyl Petition 870250086442, dated 09 / 24 / 2025, p. 65 / 530 4 / 114 3- to 20-membered, 4 to 20-membered heterocycloalkenyl, C6-20 aryl and 5 to 20-membered heteroaryl;

[0015] ring E is selected from the group consisting of C3-20 cycloalkyl, 5- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl;

[0016] L1 is selected from the group consisting of a single bond, -N(Rb1)-, HN. / θ N(Rb1)C(=O)-, -O-, -S-, -(CRb2Rb3)t-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and

[0017] L2 is selected from the group consisting of a single linkage, -N(Rb1)-, HN. '9 N(Rb1)C(=O)-, -O-, -S-, -(CRb2Rb3)t-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and

[0018] each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, characterized in that the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0019] Alternatively, two Ri are connected together to form a C3-20 cycloalkyl group, a 3- to 20-membered heterocycloalkyl group, a C6-20 aryl group, or a 5- to 20-membered heteroaryl group;

[0020] !l is II, and is tt

[0021] Alternatively, II is । , andR2 is R;

[0022] when II is II, T is C; TT

[0023] when 11 is । , T is selected from the group consisting of N and CH;

[0024] when 'R2 is R2, R2 is selected from the group consisting of H, F, Cl, Br, OH, N(Rb4) 2, CN, SF5, CHO, COOH, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C6-20 aryl, and 5- to 20-membered heteroaryl, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4 to 20-membered heterocycloalkenyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally substituted by 1, 2 or 3 R; Petition 870250086442, dated 09 / 24 / 2025, p. 66 / 530 5 / 114

[0025] when 'Rzé ^ , R2 is selected from the group consisting of O and S;

[0026] R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R;

[0027] Alternatively, R3 and R4 are linked together to form a 3- to 20-membered C3-20 cycloalkyl or heterocycloalkyl group, wherein the 3- to 20-membered C3-20 cycloalkyl or heterocycloalkyl group is optionally replaced by 1, 2 or 3 R;

[0028] each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, SF5, CN, Cho, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0029] Alternatively, two R5s are connected to each other to form a C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C6-20 aryl or 5- to 20-membered heteroaryl group, characterized in that the C320 cycloalkyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C6-20 aryl and 5- to 20-membered heteroaryl groups are optionally replaced by 1, 2 or 3 Rs;

[0030] each R6 is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0031] Alternatively, two R6 are connected to each other to form a 3- to 20-membered C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl or 5- to 20-membered heteroaryl group, characterized in that the C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0032] each R7 is independently selected from the group consisting of H, F, Cl, Br, OH, Petition 870250086442, dated 09 / 24 / 2025, p. 67 / 530 6 / 114 N(Rb4) 2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0033] R8 is selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R;

[0034] each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R;

[0035] Rb1 is selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0036] Rb2 and Rb3 are each independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R;

[0037] Alternatively, Rb2 and Rb3 are linked together to form a 3- to 20-membered C3-20 cycloalkyl or heterocycloalkyl group;

[0038] Rb4 is independently selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R;

[0039] m, n, p, qet are each independently selected from the group consisting of 0, 1, 2 and 3; Petition 870250086442, dated 09 / 24 / 2025, p. 68 / 530 7 / 114

[0040] each R is independently selected from the group consisting of H, F, Cl, Br, I, O -THE OH, NH2, CN, SF5, CHO, COOH, NH2, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R';

[0041] R' is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CH3CF3, C2H5, -4° CN, SF5, Cho, COOH and NH?;

[0042] C1-6 heteroalkyl, C1-20 heteroalkyl, 3- to 20-membered heterocycloalkyl, 4- to 20-membered heterocycloalkenyl, 5- to 20-membered heteroaryl or 5- to 10-membered heteroaryl contains 1, 2 or 3 heteroatoms or groups of heteroatoms selected independently from the group consisting of -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2 and NO.

[0043] In some embodiments of the present disclosure, ring A is selected from the group consisting of 5- to 6-membered phenyl and heteroaryl groups, wherein the 5- to 6-membered phenyl and heteroaryl groups are optionally replaced by 1, 2 or 3 Ra groups;

[0044] ring B is selected from the group consisting of C3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C5-6 cycloalkenyl, 5- to 6-membered heterocycloalkenyl, C6-10 aryl and 5- to 10-membered heteroaryl;

[0045] ring C is selected from the group consisting of C6-10 aryl and heteroaryl 5-10 members;

[0046] Ring D is selected from the group consisting of C3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, C6-10 aryl and 5- to 10-membered heteroaryl;

[0047] Ring E is selected from the group consisting of C3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C6-10 aryl and 5- to 10-membered heteroaryl;

[0048] L1 is selected from the group consisting of a single linkage, -N(Rb1)-, -O-, -S-, HN. <9 C(Rb2)2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and

[0049] L2 is selected from the group consisting of a single link, -N(Rb1)-, -O-, -S-, Petition 870250086442, dated 09 / 24 / 2025, page 69 / 530 8 / 114 HN. '9 C(Rb2)2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, eS;

[0050] each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0051] Rb1 is selected from the group consisting of 3- to 6-membered H, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and heterocycloalkyl, wherein the 3- to 6-membered C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0052] each Rb2 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0053] each R1 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0054] Alternatively, two Ri are connected together to form a 4-6 membered C4-6 cycloalkyl or heterocycloalkyl group;

[0055] Ί is H, and it is ;

[0056] Alternatively, II is 1, and R2 is R;

[0057] when II is II, T is C; TT

[0058] when II is 1, T is selected from the group consisting of N and CH;

[0059] when 'R2 R2R2 is selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; Petition 870250086442, dated 09 / 24 / 2025, p. 70 / 530 9 / 114

[0060] whenR2 is K, R2 is selected from the group consisting of O and S;

[0061] each R3 and R4 are independently selected from the group consisting of H, F,Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;

[0062] Alternatively, R3 and R4 are linked together to form a 3- to 6-membered C3-6 cycloalkyl or heterocycloalkyl group, wherein the 3- to 6-membered C3-6 cycloalkyl or heterocycloalkyl group is optionally replaced by 1, 2 or 3 R;

[0063] each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, SF5, CN, HC(=O)- C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and heterocycloalkyl of 3 to 6 members, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and heterocycloalkyl of 3 to 6 members are optionally replaced by 1, 2 or 3 R;

[0064] Alternatively, two R5s are connected together to form a 4- to 6-membered C4-6 cycloalkyl or heterocycloalkyl group, wherein the 4- to 6-membered C4-6 cycloalkyl and heterocycloalkyl are optionally replaced by 1, 2 or 3 Rs;

[0065] each R6 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0066] Alternatively, two R6 are connected together to form a 4- to 6-membered C4-6 cycloalkyl or heterocycloalkyl group, wherein the 4- to 6-membered C4-6 cycloalkyl and heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0067] each R7 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0068] R8 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R; Petition 870250086442, dated 09 / 24 / 2025, p. 71 / 530 10 / 114

[0069] m, n, peq are each independently selected from the group consisting of 0, 1, 2 and 3;

[0070] each R is independently selected from the group consisting of H, F, Cl, Br, I, THE -THE OH, NH2, CN NH2, cooh, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 alkylamino, wherein C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino is optionally substituted by 1, 2 or 3 R';

[0071] R' is selected from the group consisting of F, Cl, Br, I, OH, NH2 and CH3;

[0072] C1-6 heteroalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, 5- to 6-membered heteroaryl or 5- to 10-membered heteroaryl contains 1, 2 or 3 heteroatoms or groups of heteroatoms independently selected from the group consisting of -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and NO.

[0073] In some forms of this disclosure, each R is independently -A selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH,NH2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, -C1-6 alkyl-C1-6 alkoxy, -C1-6 alkylC1-6 alkylthio, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, -C(=O)-C1-6 alkyl, C1-6 alkyl-C(=O)-C1-6 alkyl, -NH-C(=O)-C1-6 alkyl, C1-6 alkyl-NH-C(=O)-C1-6 alkyl, -NHS(=O)2-C1-6 alkyl, C1-6 alkyl-NH-S(=O)2-C1-6 alkyl, C3-6, cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiopyranyl,

[0074] wherein C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, -C1-6 alkyl-C1-6 alkoxy, -C1-6 alkyl-C1-6 alkylthio, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, -C (=O)-C1-6 alkyl, C1-6 alkyl-C(=O)-C1-6 alkyl, -NH-C(=O)-C1-6 alkyl, C1-6 alkyl-NH-C (=O)-C1-6 alkyl, -NH-S (=O)2-C1-6 alkyl, C1-6 alkyl-NH-S (=O)2-C1-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinil, pyrazinil, tienil, pirrolil, pirazolil, imidazolil, triazolil, piperidinil, piperazinil, piranil, furanil, thiazolil, oxazolil and thiopyranil are optionally replaced by 1, 2 or 3 R' and other variables are as defined in this disclosure.

[0075] In some forms of this disclosure, each R is independently Petition 870250086442, dated 09 / 24 / 2025, p. 72 / 530 11 / 114 selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, O -HNH2, CH3, CF3, CHF2, CH2F, CFiCl, CF2Br, CF2I, O, N, and other variables are as defined in this disclosure.

[0076] In some embodiments of this disclosure, R is selected from the group that O AH consists of H, F, Cl, Br, OH, NH2, COOH, NH2, Me, CF3, CHF2, CH2F, o, N, and other variables as defined in this disclosure.

[0077] In some embodiments of this disclosure, ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, tienyl, thiazolyl, oxazolyl, isoxazolyl, 1-himidazolyl, 1H-pyrazolyl and 1H-pyrrolyl, wherein phenyl, pyridyl, pyridazinyl, pyrimidinyl, tienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl and 1H-pyrrolyl are optionally replaced by 1, 2 or 3 Ra and other variables are as defined in this disclosure.

[0078] In some embodiments of the present disclosure, ring A is selected from the group consisting of , eRa, and other variables are as defined in this disclosure.

[0079] In some embodiments of the present disclosure, each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , / , — / , hn— _ r>-- I [ Γ~ίr- o--0' hn— Γν-- !>- / , · ,ο, I—I , e0, where Me / , / , — / , / ,^,° , n' o1—1, e0 are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0080] In some embodiments of the present disclosure, each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, CF3, F, FF Petition 870250086442, dated 09 / 24 / 2025, p. 73 / 530 12 / 114 as defined in this disclosure. , and other variables are

[0081] In some embodiments of the present disclosure, ring A is selected from the group consisting of and other variables are as defined in this disclosure.

[0082] In some embodiments of the present disclosure, when R₁ is R₂, R₂ is selected from the group consisting of H, F, Cl, Br, OH, NH₂, CN, SF₅, CHO, COOH, C₁₆ alkyl, C₁₆ alkoxy, C₁₆ alkylthio, C₁₆ alkylamino, C₂₆ alkenyl, C₂₆ alkynyl, C₃₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, C₄₆ cycloalkenyl, 4- to 6-membered heterocycloalkenyl, C₆₁₀ aryl and 5- to 10-membered heteroaryl, wherein the C₁₆ alkyl, C₁₆ alkoxy, C₁₆ alkylthio, C₁₆ alkylamino, C₂₆ alkenyl, C₂₆ alkynyl, C₃₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, C₄₆ Cycloalkenyl, 4- to 6-membered heterocycloalkenyl, C6-10 aryl and 5- to 10-membered heteroaryl are optionally replaced by 1, 2 or 3 R and other variables are as defined in this disclosure.

[0083] In some embodiments of the present disclosure, when R2 is R2, R2 is selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , / , — / , hn— _ r>-- I ( Γ~ίr- o--0' hn— Γν-- !>- / , · , ° , I—I , e0, wherein Me / , / , — / , / , , ° , n' O1—1, e0 are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0084] In some embodiments of this disclosure, R2 is selected from the group that .. .. θ'consists of H, F, Cl, Br, OH, NH2, CN, Me, CF3 Γ, ^,^, / °, °, % f , \z / HN— N— __ --- I í I í / , / , ' , ° ,1—1,0, and other variables are as defined in this disclosure. Petition 870250086442, dated 09 / 24 / 2025, p. 74 / 530 13 / 114

[0085] In some forms of this disclosure, the structural fraction the selected from the group consisting of variables are r. , and 'a, and others ,,as defined in this disclosure.

[0086] In some forms of this disclosure, the structural fraction the selected THE of the group that consists of the , and other variables are as defined in this disclosure.

[0087] In some embodiments of the present disclosure, each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, -C1-6 alkyl-C1-6 alkoxy, -C1-6 alkyl-C1-6 alkylthio, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, C1-6 alkyl-C(=O)-, C1-6 alkyl-C(=O)-C1-6 alkyl, C1-6 alkyl-OC(=O)-, C1-6 alkyl-OC(=O)-C1-6 alkyl, -NH-C(=O)-C1-6 alkyl, C1-6 alkyl Petition 870250086442, 09 / 24 / 2025, pág. 75 / 530 14 / 114 NH-C (=O) -Ci-6 alquil, Ci-6 alquil-S(=O)2-, Ci-6 alquil-S(=O)2-Ci-6 alquil, -NH-S (=O)2-Ci-6 alquil, Ci-6 alquil-NH-S (=O)2-Ci-6 alquil, C3-6 cycloalquil, C3-6 cycloalquil-S(=O)2- and heterocycloalquil of 3 to 6 members,

[0088] em que o Ci-6 alquil, Ci-6 alcoxi, Ci-6 alquiltio, Ci-6 alquilamino, -Ci-6 alquil-Ci-6 alcoxi, -Ci-6 alquil-Ci-6 alquiltio, -Ci-6 alquil-Ci-6 alquilamino, Ci-6 alquil-OH, Ci-6 alquil-NH2, Ci-6 alquil-C(=O)-, Ci-6 alquil-C(= O)-Ci-6 alquil, Ci-6 alquil-OC(= O)-, Ci-6 alquil-OC(=O)Ci-6 alquil, -NH-C(=O)-Ci-6 alquil, Ci-6 alquil-NH-C (=O)-Ci-6 alquil, Ci-6 alquil-S(=O)2-, Ci6 alquil-S(=O)2-Ci-6 alquil, -NH-S (=O)2-Ci-6 alquil, Ci-6 alquil-NH-S (= O)2-Ci-6 alquil, C3-6 cycloalquil, C3-6 cycloalquil-S(=O)2- and heterocycloalquil of 3 to 6 members are optionally substituted for i, 2 or 3 R, and others varies as defined in this disclosure.

[0089] In some embodiments of the present disclosure, each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Ci-3 alkyl, Ci-3 alkoxy, Ci-3 alkylthio, Ci-3 alkylamino, Ci-3 alkyl-C(=O)-, Ci-3 alkyl-OC(=O)-, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl and C3-6 cycloalkyl-S(=O)2-, where Ci-3 alkyl, Ci-3 alkoxy, Ci-3 alkylthio, Ci-3 alkylamino, Ci-3 alkyl-C(=O)-, Ci-3 alkyl-OC(=O)-, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl and C3-6 cycloalkyl-S(=O)2- are optionally replaced by i, 2 or 3 R and other variables are as defined in the present disclosure.

[0090] In some embodiments of the present disclosure, each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, ' ,F, / , o F ß Λ\ \, / — o \ V-- OS--e___FΛH0C <í P^' °n + ' · ~ / o , / , / , ^ , / , e o , and other variables are as defined in this disclosure.

[0091] In some embodiments of the present disclosure, each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , f , / o F ß Λ r~ p \ >- °õs / , o , / , / , e - , and other variables are as defined in this disclosure.

[0092] In some embodiments of this disclosure, ring B is selected from the group Petition 870250086442, dated 09 / 24 / 2025, p. 76 / 530 15 / 114 which consists of cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyran-2keto, phenyl, pyridyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,1-dioxo-3,6-dihydro-2Hthiopyranyl, oxepinil, azetidinyl, 2-oxa-7-azaspiro[4.4]nonanil and hexa-hydro-1H-furo[3,4c]pyrrolil and other variables are as defined in this disclosure.

[0093] In some embodiments of the present disclosure, ring B is selected from the group consisting of cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyran-2-keto, phenyl, pyridyl and pyrrolidinyl and other variables are as defined in the present disclosure.

[0094] In some forms of this disclosure, the structural fraction selected from the group consisting of and other variables as defined in this disclosure.

[0095] In some forms of this disclosure, the structural fraction selected from the group consisting of o- Petition 870250086442, dated 09 / 24 / 2025, p. 77 / 530 16 / 114 , and other variables are as defined in this disclosure.

[0096] In some embodiments of the present disclosure, each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, CHO, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0097] Alternatively, two R5s are connected together to form a C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl, C6-10 aryl or 5- to 10-membered heteroaryl group, wherein the C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl, C6-10 aryl and 5- to 10-membered heteroaryl groups are optionally replaced by 1, 2 or 3 Rs and other variables are as defined in this disclosure.

[0098] In some embodiments of the present disclosure, each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, CHO, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl are optionally replaced by 1, 2 or 3 R;

[0099] Alternatively, two R5s are connected together to form a C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl, C6-10 aryl or 5- to 10-membered heteroaryl group, wherein the C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl and C6-10 aryl groups are optionally replaced by 1, 2 or 3 Rs and other variables are as defined in this disclosure.

[0100] In some versions of this disclosure, each R5 is independently Petition 870250086442, dated 09 / 24 / 2025, p. 78 / 530 17 / 114 selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, Me, CHO, , / O, HN— |\ _ Γ>- rY Πr_.oO- HN— / , · .0, and I—I ,0, where the Me, ^, / , — / , / , e0 are optionally replaced by 1, 2 or 3 R;

[0101] Alternatively, two R5s are connected together to form oa in which the xH , H z <sn' <Ní vfN,N'', e são opcionalmente substituídos por 1, 2 ou 3 R, e outras variáveis são como definidas na presente divulgação.

[0102] In some embodiments of the present disclosure, each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, Me, HC(=O)-, C ,o._ o-- HN— i\ _ r>- rY ΓI' , _ o-- HN— ,^, / ,^,° , and , , where Me, , , , , ,0, I—í , and are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0103] In some embodiments of the present disclosure, each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, SF5, CN, Me, CF3, CHO, / ,

[0104] Alternatively, two R5s are connected together to form HN,, HZ zt \ Cl—JN, ouNv, and other variables are as defined in this disclosure. Petition 870250086442, dated 09 / 24 / 2025, p. 79 / 530 18 / 114

[0105] In some embodiments of the present disclosure, each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, SF5, CN, Me, CF3, HC(=O)-, Other variables are as defined in this disclosure.

[0106] In some embodiments of the present disclosure, ring C is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and tienyl, and other variables are as defined in the present disclosure.

[0107] In some versions of this disclosure, the structural fraction is selected from the group consisting of F Petition 870250086442, dated 09 / 24 / 2025, p. 80 / 530 19 / 114 Cl^ J 7 and other variables as defined in this disclosure. •'δ

[0108] In some forms of this disclosure, the structural fraction selected from the group consisting of Variables are as defined in this disclosure. and others

[0109] In some embodiments of the present disclosure, each Rô is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , / , —' , / N, ^, □ , and , wherein Me / , / o, ,H / N, O, c^”, rY Q1—1, and O are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0110] In some forms of this disclosure, each Rô is independently Petition 870250086442, dated 09 / 24 / 2025, p. 81 / 530 20 / 114 selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, CF3 / and other variables as defined in this disclosure.

[0111] In some embodiments of the present disclosure, ring D is selected from the group consisting of x X9 XX X10 T3 Me me ^^4 .*7 x8,

[0112] T1, T2, T3 and T4 are each independently selected from the group consisting of N and CH;

[0113] X1, X2, X3 and X4 are each independently selected from the group consisting of a single bond and CH2;

[0114] X5 and Xô are each independently selected from the group consisting of a single bond, CH2 and CH2CH2, and X5 and Xô are not simultaneously a single bond;

[0115] X7, Xs, X9 and X10 are each independently selected from the group consisting of a single bond, NH, O, S, CH2 and ''en'o, and no more than four of X7, Xs, X9 and X10 are single bonds simultaneously;

[0116] La is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl and C1-6 heteroalkyl, wherein the C1-6 alkyl and C1-6 heteroalkyl are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0117] In some embodiments of the present disclosure, ring D is selected from the group consisting of ,X9 X10 t3í ' h1 1,''T4χ^Χ7 '' , e8, and other variables are as defined in this disclosure.

[0118] In some embodiments of this disclosure, ring D is selected from the group Petition 870250086442, dated 09 / 24 / 2025, p. 82 / 530 21 / 114 which consists of N— Γ , '' , and other variables are as defined in this disclosure.

[0119] In some embodiments of the present disclosure, ring D is selected from the group consisting of piperidinyl, piperazinyl and 1,2,3,6-tetrahydropyridinyl, and other variables are as defined in the present disclosure.

[0120] In some forms of this disclosure, the structural fraction selected from the group consisting of and other variables are as defined in this disclosure.

[0121] In some forms of this disclosure, the structural fraction selected from the group consisting of , and other variables are as defined in this disclosure.

[0122] In some forms of this disclosure, each R7 is independently Petition 870250086442, dated 09 / 24 / 2025, p. 83 / 530 22 / 114 / -——' II'· selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , / ,— / , / , ,0^ O' , andO' , wherein MeC , / °,— / , / ,^,0^ JO , and are optionally replaced by 1, 2 or 3 R, and other variables are as defined in this disclosure.

[0123] In some forms of this disclosure, each R7 is independently -selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, CF3 C, f, ff, and other variables as defined in this disclosure.

[0124] In some embodiments of the present disclosure, ring E is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and tienyl, and other variables are as defined in the present disclosure.

[0125] In some embodiments of the present disclosure, the structural fraction R7q is selected from the group consisting of Oh oh oh OH OH OH OH φ φ φ / φ f , ci , Br , 1 , and other variables are as defined in this disclosure.

[0126] In some embodiments of the present disclosure, the structural fraction R7q is selected from the group consisting of OH Petition 870250086442, dated 09 / 24 / 2025, p. 84 / 530 23 / 114 OH OH and other variables as defined in this disclosure.

[0127] In some embodiments of the present disclosure, R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me / / ”,— / , / ,0,el—I , o , where the Me,Ã and are optionally replaced by 1, 2, or 3 R, and other variables are as defined in this disclosure.

[0128] In some embodiments of the present disclosure, each R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, ___ ___ \ / / _r-F< o- p-ftC hn- n- _r>- π Π. CF3 / , f , ff / ,— / ,Ff , / / ​​​​,1^ ,0 ,1—I ,ο-1, and other variables are as defined in this disclosure.

[0129] In some embodiments of the present disclosure, R8 is selected from the group consisting of H, Me, f, ^,0, í, e0, wherein Me Ã, ^,0,1—1, e0 are optionally replaced by 1, 2 or 3 Rs, and other variables are as defined in the present disclosure.

[0130] In some embodiments of the present disclosure, R8 is selected from the group that r--FHf 1—íz1 consists of H, Me, CF3, / ,F।:, · . o ,1—1 , e0, and other variables are as defined in this disclosure.

[0131] The present disclosure also provides a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of: Petition 870250086442, dated 09 / 24 / 2025, p. 85 / 530 24 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 86 / 530 25 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 87 / 530 26 / 114 OH Petition 870250086442, dated 09 / 24 / 2025, p. 88 / 530 27 / 114 OH Petition 870250086442, dated 09 / 24 / 2025, p. 89 / 530 28 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 90 / 530 29 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 91 / 530 30 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 92 / 530 31 / 114 OH Petition 870250086442, dated 09 / 24 / 2025, p. 93 / 530 32 / 114 Petition 870250086442, dated 09 / 24 / 2025, p. 94 / 530 33 / 114

[0132] In another aspect of this disclosure, this disclosure also provides a pharmaceutical composition. In some embodiments of this disclosure, the pharmaceutical composition comprises the aforementioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments of this disclosure, the pharmaceutical composition also includes a pharmaceutically acceptable excipient.

[0134] In yet another aspect of the present disclosure, the present disclosure further provides a use of the compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof or of the pharmaceutical composition in the manufacture of a medicament for the treatment of a disease associated with a tumor.

[0135] One objective of the present disclosure is to provide a compound as a WRN inhibitor, or a pharmaceutically acceptable stereoisomer, deuterated derivative, solvate, prodrug, metabolite, salt or cocrystal thereof, and intermediates and methods of preparation thereof, as well as the use thereof in the manufacture of a medicament for the treatment of a disease associated with a highly microsatellite unstable tumor.

[0136] In some embodiments of this disclosure, the disease associated with the tumor is one or more of the diseases associated with solid tumors.

[0137] The compounds in this disclosure can be used alone or in combination with other chemotherapeutic drugs, targeted therapies, or immunotherapeutic drugs for the treatment of various tumors, particularly malignant tumors with high microsatellite instability (MSI) or malignant tumors with repair deficiency. Petition 870250086442, dated 09 / 24 / 2025, p. 95 / 530 34 / 114 mismatch (dMMR) or malignant tumors detected with a high number of repeat sequences (TA)n, including but not limited to colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer and the like.

[0138] Definition and description

[0139] Unless otherwise specified, the following terms and phrases, when used in this document, have the following meanings. A specific term or phrase should not be considered undefined or unclear in the absence of a particular definition, but should be understood in its common meaning. When a trade name appears in this document, it is intended to refer to its corresponding merchandise or active ingredient thereof.

[0140] The term pharmaceutically acceptable is used in this document in terms of those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of reliable medical judgment, without excessive toxicity, irritation, an allergic reaction, other problems or complications, proportionate to a reasonable benefit / risk ratio.

[0141] The term pharmaceutically acceptable salt refers to a salt of the compound of the present disclosure that is prepared by reacting the compound with a specific substituent of the present disclosure with a relatively non-toxic acid or base. When the compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base addition salt includes a sodium, potassium, calcium, ammonium, organic amine, magnesium, or similar salt. When the compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a solution or a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include an inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid. Petition 870250086442, dated 09 / 24 / 2025, page 96 / 530 35 / 114 hydrogen sulfate, hydroiodic acid, phosphorous acid; and an organic acid salt, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; and amino acid salts (such as arginine) and an organic acid salt, such as glucuronic acid. Certain specific compounds of this disclosure contain both basic and acidic functional groups, therefore they can be converted into either base or acid addition salt.

[0142] The pharmaceutically acceptable salt of this disclosure can be prepared from the parent compound containing an acidic or basic moiety by a conventional chemical method. Generally, such a salt can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate acid or base in water or an organic solvent or a mixture thereof.

[0143] The compounds of this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure covers all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomeric isomers, (D)-isomers, (L)-isomers and racemics and other mixtures thereof, such as enantiomers or enriched diastereomeric mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and their mixtures are included within the scope of this disclosure.

[0144] Unless otherwise specified, the term tautomer or tautomeric form means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can be rapidly transformed into one another. If tautomers possibly exist (as in solution), chemical equilibrium of the tautomers can be achieved. For example, the proton tautomer (also called the prototropic tautomer) comprises interconversion through proton migration, such as keto-enol isomerization and imine-enamine isomerization. The valence tautomer comprises some recombination of bonding electrons for mutual transformation. A Petition 870250086442, dated 09 / 24 / 2025, page 97 / 530 36 / 114 A specific example of keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0145] The compound of this disclosure may contain an unnatural ratio of atomic isotope in one or more of an atom constituting the compound. For example, the compound may be radiolabeled with a radioactive isotope, such as tritium (3H), iodine-125 (125I), or C-14 (14C). By another example, deuterated drugs may be formed by replacing hydrogen with deuterium; the bond formed by deuterium and carbon is stronger than that of ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic and side effects, greater drug stability, improved efficacy, prolonged biological half-life of drugs, and the like. All isotopic variations of the compound of this disclosure, whether radioactive or not, are encompassed within the scope of this disclosure.

[0146] Optionally or optionally means that the subsequent event or condition may occur, but is not required, and the description includes the case where the event or condition occurs and the case where the event or condition does not occur.

[0147] The term replaced by... means that one or more hydrogen atoms on a specific atom are replaced by the substituent, including deuterium and hydrogen variables, provided that the valence of the specific atom is normal and the substituted compound is stable. The term optionally replaced by... means that an atom may or may not be substituted, unless otherwise specified, the type and number of substituents may be arbitrary, provided they are chemically attainable.

[0148] When any variable (such as R) occurs in the constitution or structure of the compound more than once, the definition of the variable in each occurrence is independent. Thus, for example, if a group is substituted by 1, 2, or 3 R, the group may optionally be substituted by up to three R, where the definition of R in each occurrence is independent. Furthermore, a combination of the substituent and / or its variant is permitted only when Ra Rb o -¼ the combination results in a stable compound. For example, Ra Rb may be selected Petition 870250086442, dated 09 / 24 / 2025, page 98 / 530 37 / 114F0 NH2O of the group consisting of OH, etc.

[0149] When one of the variables is a single link, this means that the two groups linked by the single link are directly linked. For example, when L2 in It represents a simple connection; the structure is actually... IJT2. A hyphen () not between two letters or symbols indicates the attachment site of a substituent. For example, C1-6 alkylcarbonyl- refers to a C1-6 alkyl group bonded to the rest of the molecule via a carbonyl group. However, when the attachment site of a substituent is obvious to those skilled in the art, for example, a halogen substituent, it may be omitted.

[0150] Unless otherwise specified, when the valence bond of a group has a dashed line '', as in , the dashed line indicates the group's binding site to the rest of the molecule.

[0151] When the listed substituents do not indicate through which atom it is attached to the substituted group, this substituent may be attached through any atom, for example, pyridyl, as a substituent, may be attached to the substituted group through any carbon atom in the pyridine ring.

[0152] When the listed linking group does not indicate the direction for linking, the direction for linking is arbitrary, for example, the linking group L contained in So, it can link phenyl and cyclopentyl to form in the same direction as the left-to-right reading order and can link phenyl and cyclopentyl to form in the opposite direction to the left-to-right reading order. A combination of the linking groups, substituents and / or variables thereof is permitted only when such a combination can result in a stable compound.

[0153] Unless otherwise specified, the number of atoms in a ring refers to the count of atoms that constitute the ring itself in compounds formed by bonding. Petition 870250086442, dated 09 / 24 / 2025, p. 99 / 530 38 / 114 atomic in cyclic structures (such as monocyclic compounds, fused ring compounds, spiro compounds, bridging ring compounds, cross-linked compounds, carbocyclic compounds, and heterocyclic compounds). The number of atoms in a ring is generally defined as the number of ring members, for example, a 4- to 6-membered ring refers to a ring in which 4 to 6 atoms are arranged around it. When a ring is replaced by a substituent, the atoms contained in the substituent are not included in the ring-forming atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0154] Unless defined otherwise, the term alkyl refers to a saturated hydrocarbon group comprising primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or combinations thereof, which may represent a linear and / or branched alkyl group, and which may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methyne). Unless specifically indicated otherwise in the descriptive report, alkyl may be optionally substituted.

[0155] Unless otherwise specified, the term C1-20 alkyl refers to a linear or branched saturated hydrocarbon group consisting of 1 to 20 carbon atoms. C120 alkyl includes C1-19, C1-15, C1-10, C1-5, C1-4, C2-20, C2-12, C2-6 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methyne). Examples of C1-20 alkyl include, but are not limited to, methyl, ethyl, n-propyl, sec-butyl, n-pentyl, n-hexyl, 1-methylhexyl, n-nonyl, n-decyl, adamantil, n-undecyl, n-dodecyl, 2-ethyldodecyl, 2-butyldodecyl, n-eicosyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene, 1,12-dodecylene, 1,14-tetradecylene, 1,16-hexadecylene, 1,18-octadecylene, 1,20-eicosylene, etc.

[0156] Unless otherwise specified, the term C1-6 alkyl refers to a linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. C1-6 alkyl includes C1-5 alkyl, C1-4 alkyl, C2-6 alkyl, etc.; it can be monovalent (like methyl), divalent (like methylene), or multivalent (like methyne). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl, such as n-propyl (n-Pr). Petition 870250086442, dated 09 / 24 / 2025, p. 100 / 530 39 / 114 or isopropyl (i-Pr), butyl, such as n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu) or tert-butyl (t-Bu), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5pentylene, 1,6-hexylene, etc.

[0157] Unless otherwise specified, the term C1-3 alkyl refers to a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. C1-3 alkyl includes C1-2 alkyl, C2-3 alkyl, etc.; it can be monovalent (like methyl), divalent (like methylene), or multivalent (like methyne). Examples of C1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), methylene, 1,2-ethylene, 1,3-propylene, etc.

[0158] Unless otherwise specified, the term alkenyl refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, which may represent a linear and / or branched alkenyl group, wherein branched means one or more alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkenyl chain. It may be monovalent, divalent or multivalent. Unless specifically indicated otherwise in the descriptive report, alkenyl may optionally be substituted.

[0159] Unless otherwise specified, C2-20 alkenyl refers to a linear or branched hydrocarbon group consisting of 2 to 20 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. C2-20 alkenyl includes C2-19, C2-15, C2-10, C2-5, C2-4, C3-20, C4-12, C5-6 alkenyl, etc.; it can be monovalent, divalent, or multivalent.Examples of C2-20 alkenyl groups include, but are not limited to, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, octenyl, decenyl, n-undecenyl, vinylene, propenylene, sec-butenylene, 2-methylbutenylene, etc.

[0160] Unless otherwise specified, C2-6 alkenyl refers to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. C2-6 alkenyl includes C2-4 alkenyl, C2-3 alkenyl, C4 alkenyl, C3 alkenyl, C2 alkenyl, etc.; it may be monovalent, divalent, or multivalent. Examples of C2-6 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, Petition 870250086442, dated 09 / 24 / 2025, p. 101 / 530 40 / 114 hexenyl, butadienyl, pentadienyl, hexadienyl, vinylene, propenylene, sec-butenylene, etc.

[0161] Unless otherwise specified, C2-3 alkenyl refers to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located in any position of the group. C2-3 alkenyl includes C3 and C2 alkenyl; C23 alkenyl may be monovalent, divalent, or multivalent. Examples of C2-3 alkenyl include, but are not limited to, vinyl, propenyl, vinylene, propenylene, etc.

[0162] Unless otherwise specified, the term alkynyl refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which may represent a linear and / or branched alkynyl group, where branched means one or more alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkynyl chain. It may be monovalent, divalent or multivalent. Unless specifically indicated otherwise in the descriptive report, the alkynyl may be optionally substituted.

[0163] Unless otherwise specified, the term C2-20 alkynyl refers to a linear or branched hydrocarbon group consisting of 2 to 20 carbon atoms containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be located at any position in the group. C2-20 alkynyl includes C2-19, C2-15, C2-10, C25, C2-4, C3-20, C4-12, C5-6 alkynyl, etc.; it may be monovalent, divalent, or multivalent. Examples of C2-20 alkynyl include, but are not limited to, ethinyl, propynyl, ethynylene, propynylene, penthynyl, pentylene, 1-butynyl, butadiinyl, cyclopropylethynyl, 3-methyl-2-pentynylene, etc.

[0164] Unless otherwise specified, the term C2-6 alkynyl refers to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be located in any position of the group. It may be monovalent, divalent, or multivalent. C2-6 alkynyl includes C2-5, C2-4, C2-3, C2, C2-6, C6, and C5 alkynyl, etc. Examples of C2-6 alkynyl include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, penthynyl, pentylene, etc.

[0165] Unless otherwise specified, C2-3 alkynyl refers to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least Petition 870250086442, dated 09 / 24 / 2025, p. 102 / 530 41 / 114 minus one carbon-carbon triple bond, and the carbon-carbon triple bond can be located anywhere in the group. It can be monovalent, divalent, or multivalent. The C2-3 alkynyl group includes C3 and C2 alkynyl groups. Examples of C2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, etc.

[0166] Unless otherwise specified, the term heteroalkyl by itself or in combination with another term refers to a stable linear or branched alkyl radical or combination thereof, consisting of a specified number of carbon atoms and at least one heteroatom or heteroatom group, wherein alkyl in alkyl radical is as defined above in this disclosure. In some embodiments, the heteroatom is selected from the group consisting of B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from the group consisting of -C(=O)O-, C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and S(=O)N(H)-. In some embodiments, the heteroalkyl is C1-20 heteroalkyl; in some embodiments, the heteroalkyl is C1-6 heteroalkyl; in other embodiments, the heteroalkyl is C1-3 heteroalkyl.The heteroatom or heteroatom group can be located in any internal position of the heteroalkyl, including the position where the alkyl is connected to the rest of the molecule. Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2CH3, etc.; Up to two heteroatoms may be consecutive, such as CH2-NH-OCH3. Unless specifically indicated otherwise in the descriptive report, the heteroalkyl may optionally be substituted. Unless otherwise specified, the term alkoxy refers to an alkyl group that is linked to the rest of the molecule through an oxygen atom, wherein alkyl in the alkyl group is as defined above in this disclosure.Unless specifically indicated otherwise in the descriptive report, alkoxy may optionally be substituted.

[0167] Unless otherwise specified, the term C1-20 alkoxy refers to a group Petition 870250086442, dated 09 / 24 / 2025, p. 103 / 530 42 / 114 alkyl containing 1 to 20 carbon atoms that is connected to the rest of the molecule through an oxygen atom. C1-20 alkoxy includes C1-19, C1-10, C1-5, C2-20, C2-8, C1, C5, C4 alkoxy, etc. Examples of C1-20 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, 5-butoxy and t-butoxy), pentylox (including n-pentylox, isopentylox and neopentylox), hexyloxy, n-hexyloxy, 1-methylhexyloxy, n-nonyloxy, n-decylox, n-undecylox, n-dodecylox, 2-ethyldodecylox, n-icosyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butylenexy, pentylenexy, heptylenexy, dodecylox, etc.

[0168] Unless otherwise specified, the term C1-6 alkoxy refers to an alkyl group containing 1 to 6 carbon atoms that is connected to the rest of the molecule through an oxygen atom. C1-e alkoxy includes C1-4, C1-3, C1-2, C2-6, C2-4, C1, C5, C4, C3 alkoxy, etc. Examples of C1-e alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentiloxy and neopentyloxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butylenexy, pentylenexy, etc.

[0169] Unless otherwise specified, the term C1-4 alkoxy refers to an alkyl group containing 1 to 4 carbon atoms that is connected to the rest of the molecule through an oxygen atom. C1-4 alkoxy includes C1-3, C1-2, C2-4, C4, C3 alkoxy, etc. Examples of C16 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methyleneoxy, ethyleneoxy, propyleneoxy, butylenexy, etc.

[0170] Unless otherwise specified, the term C1-3 alkoxy refers to an alkyl group containing 1 to 3 carbon atoms that is connected to the rest of the molecule through an oxygen atom. C1-3 alkoxy includes C1-2, C2-3, C3, C2 alkoxy, etc. Examples of C1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy, etc.

[0171] Unless otherwise specified, the term amino may be monovalent - -nh2 , divalent --NH, or multivalent--N—.

[0172] Unless otherwise specified, the term alkylamino refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, where Petition 870250086442, dated 09 / 24 / 2025, p. 104 / 530 43 / 114 alkyl in the alkyl group is as defined above in this disclosure. Unless specifically stated otherwise in the descriptive report, the alkylamino may optionally be substituted.

[0173] Unless otherwise specified, the term C1-20 alkylamino refers to an alkyl group containing 1 to 20 carbon atoms that is linked to the rest of the molecule via an amino group. C1-20 alkylamino includes C1-19, C1-14, C1-12, C2-6, C2-4, C15, C10, Cs, C5, C20 alkylamino, etc. Examples of C1-20 alkylamino groups include, but are not limited to, NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, -NHCH2CH2CH2CH2CH3, NHCH2CH2CH2CH2CH2CH3, -N(CH2CH2CH3)(CH2CH2CH2CH3), etc.

[0174] Unless otherwise specified, the term C1-6 alkylamino refers to an alkyl group containing 1 to 6 carbon atoms that is linked to the rest of the molecule via an amino group. C1-6 alkylamino includes C1-4, C1-3, C1-2, C2-6, C2-4, C6, C5, C4, C3, C2 alkylamino, etc. Examples of C1-6 alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, NHCH2CH2CH2CH3, etc.

[0175] Unless otherwise specified, the term C1-4 alkylamino refers to an alkyl group containing 1 to 4 carbon atoms that is linked to the rest of the molecule via an amino group. C1-4 alkylamino includes C1-3, C1-2, C2-4, C4, C3, C2 alkylamino, etc. Examples of C1-4 alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, NHCH2CH2CH2CH3, etc.

[0176] Unless otherwise specified, the term C1-3 alkylamino refers to an alkyl group containing 1 to 3 carbon atoms that is linked to the rest of the molecule via an amino group. C1-3 alkylamino includes C1-2, C3, C2, etc. alkylamino. Examples of C1-3 alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0177] Unless otherwise specified, the term alkylthio refers to an alkyl group that is attached to the rest of the molecule via a sulfur atom, wherein alkyl Petition 870250086442, dated 09 / 24 / 2025, p. 105 / 530 44 / 114 in the alkyl group is as defined above in this disclosure. Unless specifically stated otherwise in the descriptive report, the alkylthion may optionally be substituted.

[0178] Unless otherwise specified, the term C1-20 alkylthio refers to an alkyl group containing 1 to 20 carbon atoms that are connected to the rest of the molecule through a sulfur atom. C1-20 alkylthio includes C1-19, C1-14, C1-12, C2-6, C2-4, C15, C10, Cs, C5, C20 alkylthio, etc. Examples of C1-20 alkylthio include, but are not limited to, SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -SCH2CH2CH2CH3, -SCH2CH2(CH3)2, SCH2CH2CH2CH2CH3, -SCH2CH2CH2CH2CH2CH3, -SCH2(CH2CH2CH3)(CH2CH2CH2CH3), etc.

[0179] Unless otherwise specified, the term C1-6 alkylthio refers to an alkyl group containing 1 to 6 carbon atoms that is connected to the rest of the molecule through a sulfur atom. C1-6 alkylthio includes C1-4 alkylthio, C1-3 alkylthio, C1-2 alkylthio, C2-6 alkylthio, C2-4 alkylthio, C6 alkylthio, C5 alkylthio, C4 alkylthio, C3 alkylthio, C2 alkylthio, etc. Examples of C1-6 alkylthio include, but are not limited to, -SCH3, -SCH2CH3, SCH2CH2CH3, -SCH2(CH3)2, etc.

[0180] Unless otherwise specified, the term "C1-4 alkylthio" refers to an alkyl group containing 1 to 4 carbon atoms that is connected to the rest of the molecule through a sulfur atom. C1-4 alkylthio includes C1-3, C1-2, C2-4, C4, C3, C2 alkylthio, etc. Examples of C1-4 alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, SCH2(CH3)2, etc.

[0181] Unless otherwise specified, the term C1-3 alkylthio refers to an alkyl group containing 1 to 3 carbon atoms that is connected to the rest of the molecule through a sulfur atom. C1-3 alkylthio includes C1-3, C1-2, C3 alkylthio, etc. Examples of C1-3 alkylthiol include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0182] Unless otherwise specified, the term cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include fused, spiro and / or bridging ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, Petition 870250086442, dated 09 / 24 / 2025, p. 106 / 530 45 / 114 cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, adamantil, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. C4-6 cycloalkyl refers to a cycloalkyl group with 4 to 6 carbon atoms in the ring. Similarly, C3-4 cycloalkyl refers to a cycloalkyl group with 3-4 carbon atoms in the ring. Unless specifically indicated otherwise in the descriptive report, cycloalkyl may be optionally substituted.

[0183] Unless otherwise specified, C3-20 cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon group with 3-20 carbon atoms in the ring, for example, with 3-15 carbon atoms in the ring, for example, 3-6 carbon atoms in the ring; it may be monovalent, divalent or multivalent. Examples of C3-20 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0184] Unless otherwise specified, C3-6 cycloalkyl refers to a saturated monocyclic or bicyclic hydrocarbon group with 3-6 carbon atoms in the ring, for example, with 3-5 carbon atoms in the ring, for example, 3-4 carbon atoms in the ring; it may be monovalent, divalent or multivalent. Examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0185] Unless otherwise specified, C4-6 cycloalkyl refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms in monocyclic and bicyclic systems, and C4-6 cycloalkyl includes C4-5 cycloalkyl, C5-6 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, etc.; it may be monovalent, divalent, or multivalent. Examples of C4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0186] Unless otherwise specified, the term heterocycloalkyl refers to a non-aromatic saturated cyclic group existing as a monocyclic ring, fused ring, spiro ring and / or bridging ring, wherein at least one ring atom is a heteroatom or heteroatom group and the remainder are carbon atoms; in some embodiments, each occurrence of a heteroatom is independently selected from the group consisting of B, O, N and S, in which the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)p, where Petition 870250086442, dated 09 / 24 / 2025, p. 107 / 530 46 / 114 p is 1 or 2) and the nitrogen heteroatoms are optionally quaternized; in other embodiments, each occurrence of a heteroatom group is independently selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. The heteroatom or heteroatom group may be located at any internal position of the heterocycloalkyl, including the position where the heterocycloalkyl is connected to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3- to 20-membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl; In other embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. Unless specifically indicated otherwise in the descriptive report, the heterocycloalkyl may optionally be substituted.Unless otherwise specified, the term 3- to 6-membered heterocycloalkyl by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 atoms in the ring, wherein 1, 2, 3, or 4 atoms in the ring are heteroatoms independently selected from the group consisting of B, O, S, and N, or groups of heteroatoms as described above, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes a spiro ring, a fused ring, and a bridging ring. Furthermore, with respect to 3- to 6-membered heterocycloalkyl groups, the heteroatom or heteroatom group can be located in any internal position of the heterocycloalkyl group, including the position where the heterocycloalkyl group is connected to the rest of the molecule.3- to 6-membered heterocycloalkyl groups include 5- to 6-membered, 4-membered, 5-membered, 6-membered, etc. heterocycloalkyl groups. Examples of 3- to 6-membered heterocycloalkyl compounds include, but are not limited to, azetidinyl, oxetanil, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxolil, ditianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc. Petition 870250086442, dated 09 / 24 / 2025, page 108 / 530 47 / 114

[0187] Unless otherwise specified, the term cycloalkenyl in this disclosure refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of carbon and hydrogen atoms having one or more sp2 carbon-carbon double bonds, which may include fused, spiro and / or bridging ring systems. Monocyclic cycloalkenyl includes, but is not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl includes, but is not limited to, bicyclo[2.2.1]hept-2-enyl, etc. Unless specifically indicated otherwise in the descriptive report, cycloalkenyl may optionally be substituted. C3-7 cycloalkenyl includes C3, C4, C5, C6 and C7 cycloalkenyl. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0188] Unless otherwise specified, the term heterocycloalkenyl in this disclosure refers to a cyclic alkenyl group containing multiple heteroatoms or heteroatom groups. In some embodiments, each occurrence of a heteroatom is independently selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2) and the nitrogen heteroatoms are optionally quaternized. In other embodiments, each occurrence of a heteroatom group is independently selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH), -S(=O)2N(H)- and -S(=O)N(H)-.The term 5- to 6-membered heterocycloalkenyl, by itself or in combination with other terms, refers to an unsaturated cyclic group consisting of 5 to 6 atoms in the ring, respectively, wherein 1, 2, 3, or 4 atoms in the ring are heteroatoms independently selected from the group consisting of B, O, S, and N, or groups of heteroatoms as described above, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). Examples of heterocycloalkenyl include, but are not limited to, O, etc. Unless specifically indicated otherwise in the descriptive report, heterocycloalkenyl may optionally be substituted.

[0189] Unless otherwise specified, when a substituent is connected to ring A Petition 870250086442, dated 09 / 24 / 2025, p. 109 / 530 48 / 114 can be connected to ring A to form a ring, meaning that the substituent can be connected to any site on ring A to form a new ring with ring A, including a fused ring, a spiro ring, or a bridging ring; wherein ring A can be selected from the group consisting of cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, X heteroaryl, etc., as described above. For example, when R in can be connected n to form a 6-membered ring, examples of which include, but are not limited to IJ í k / NH l J limited to , , -', etc.

[0190] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific occurrence of n+m carbons, for example, C1-12 includes C1, C2, C3, C4, C5, C6, C7, Cs, C9, C10, C11, and C12, also includes any range from n to n+m, for example, C1-12 includes C1-3, C1-6, C1-9, C3-6, C3-9, C3-12, C6-9, C6-12, C9-12, etc.; Similarly, n-membered an + m-membered means that the number of atoms in the ring is from n+m, for example, 3-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, it also includes any range from n+m, for example, 3-membered ring includes 3-membered ring, 3-membered ring, 5-membered ring, 6-membered ring, 6-membered ring, 6-membered ring, 6-membered ring, 6-membered ring, etc.

[0191] Unless otherwise specified, the term aryl refers to a hydrocarbon ring system group containing at least one aromatic ring. In this disclosure, aryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, and / or bridging ring systems. Aryl includes, but is not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene, and groups derived therefrom. Unless specifically indicated otherwise in the descriptive report, aryl may optionally be substituted. Petition 870250086442, dated 09 / 24 / 2025, page 110 / 530 49 / 114

[0192] Unless otherwise specified, the term heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, tienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc. The heteroaryl may be connected to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring and / χθ / χθ ---I \ _ Q _ I \ Non-limiting examples of the same include: nen. Non-limiting examples of heteroaryl also include triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furanopyrrole, furanofuran, thienofuran, benzoisoxazole, benzoisothiazole, benzimidazole, quinoline, isoquinoline, naphthyridine, quinoxaline, phenanthridine, perimidine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole and derivatives thereof. Unless specifically indicated otherwise in the descriptive report, heteroaryl may optionally be substituted or unsubstituted.When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

[0193] The substituted term, as used in this disclosure, means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including but not limited to halogen atoms (such as F, Cl, Br, I), groups containing oxygen atoms (such as hydroxyl, alkoxy, ester), groups containing sulfur atoms (such as a thiol group, thioalkyl group, sulfone group, sulfonyl group or sulfinyl group), Petition 870250086442, dated 09 / 24 / 2025, p. 111 / 530 50 / 114 groups containing nitrogen atoms (such as amino, amido, alkylamino, dialkylamino, arylamino, aryl-alkyl-amino, diarylamino, N-oxide group, imido, enamino), groups containing silicon atoms (such as trialkylsilyl, dialkylarylyl, alkyldialisilyl, triarylsilyl) and other heteroatoms in various other groups.

[0194] The substituted term, as used in this disclosure, also means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), one or more hydrogen atoms are replaced by a higher-order bond (such as a double bond or triple bond) to a heteroatom, for example, oxygen in carbonyl, carboxyl and ester groups and nitrogen in imine, oxime, hydrazone and nitrile groups. For example, substituted means that one or more hydrogen atoms in any of the above groups are substituted by NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, SO2ORg, =NSO2Rg, and -SO2NRgRh.The substituted form can also mean that one or more hydrogen atoms in any of the above groups are substituted by -C(=O)Rg, C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, and -CH2SO2NRgRh. Rg and Rh are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl.The substituted group can also mean that one or more hydrogen atoms in any of the above groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. Furthermore, each of the above substituents can also be optionally replaced by one or more of the above substituents.

[0195] It will be understood by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers. Therefore, the compound has two or more Petition 870250086442, dated 09 / 24 / 2025, p. 112 / 530 51 / 114 stereoisomers. Therefore, the compounds of this disclosure may be present in the form of individual stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in arbitrary proportions, such as racemates, and under the appropriate condition, they may be present in the form of tautomers and geometric isomers thereof.

[0196] As used herein, the term stereoisomer refers to compounds that have the same chemical constitution but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers, etc.

[0197] As used herein, the term enantiomer refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0198] As used in this document, the term diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Diastereomeric mixtures can be separated by high-resolution analytical methods, such as electrophoresis and chromatography (such as HPLC separation).

[0199] Many organic compounds are present in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When optically active compounds are described, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral centers. The prefixes del or (+) and (-) are used to denote the symbols for rotationally planar polarized light of the compound, where (-) or 1 indicates that the compound is levorotatory. Compounds with a prefix of (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures.A mixture of enantiomers in a 50:50 ratio is known as a racemic mixture or racemate, which may be present in a chemical reaction or process without stereoselectivity or stereospecificity. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomers that is not optically active.

[0200] The racemic mixture can be used in its own form or after being resolved. Petition 870250086442, dated 09 / 24 / 2025, p. 113 / 530 52 / 114 in individual isomers. Resolution can produce stereochemically pure compounds or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods such as chromatography using chiral adsorbents. Individual isomers in a chiral form can be prepared from chiral precursors. Alternatively, a diastereomeric salt can be formed with a chiral acid (such as a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid) and then the mixture is chemically separated to obtain a single isomer. The salt is then graded and crystallized, and one or both of the split bases are released.This process can optionally be repeated to obtain one or two isomers that essentially do not contain the other isomer, i.e., the desired stereoisomer with an optical purity of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, the racemate can be covalently linked to a chiral (auxiliary) compound to obtain diastereomers, as is well known to those skilled in the art.

[0201] The term tautomer or tautomeric form, as used herein, refers to structural isomers of different energies that are interconvertible across a low-energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversion via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons.

[0202] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods and equivalent alternatives known to those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0203] Technical and scientific terms used in this document that are not specifically defined have the meanings commonly understood by those skilled in the art to which this disclosure pertains. Petition 870250086442, dated 09 / 24 / 2025, p. 114 / 530 53 / 114 DETAILED DESCRIPTION OF THE PREFERRED MODALITY

[0204] This disclosure This disclosure is described in detail by the examples below, but this does not mean that there are any adverse restrictions to the present disclosure. The present disclosure has been described in detail in this document and its specific embodiments have also been disclosed; to one skilled in the art, it is obvious to make various modifications and improvements to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0205] Example 1: Synthesis of Compound 1 1-6 1-7 OH

[0206] Step 1: Preparation of compound 1-2

[0207] Compound 1-1 (1.00 g, 5.81 mmol) and triphosgene (1.72 g, 5.81 mmol) were dissolved in ultradry tetrahydrofuran (50 mL). Under an ice-cold water bath and a nitrogen atmosphere, triethylamine (2.35 g, 23.2 mmol) was added dropwise to the reaction system. After the dropwise addition was complete, the reaction system was stirred under an ice-cold water bath for 1 h. Then, 4-amino-1-tert-butoxycarbonylpiperidine (2.02 g, 10.1 mmol) was added. The mixture was naturally heated to room temperature and stirred for 16 h. LCMS showed that the reaction was complete. A saturated aqueous solution of ammonium chloride (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (70 mL χ 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography (water / acetonitrile = 3 / 2) to obtain compound 1-2 (1.94 g, yield: 84.0%).LC. Petition 870250086442, dated 09 / 24 / 2025, page 115 / 530 54 / 114 MS (ESI) [M+H]+ 399.1.

[0208] Step 2: Preparation of compound 1-3

[0209] Under a nitrogen atmosphere, potassium tert-butoxide (1.35 g, 12.0 mmol) was added to a solution of compound 1-2 (800 mg, 2.01 mmol) in ultradry tetrahydrofuran (10 mL). The reaction system was stirred at 60°C for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 1-3 (338 mg, yield: 47.8%). LC-MS (ESI) [M+H]+297.0.

[0210] Step 3: Preparation of compound 1-4

[0211] Under a nitrogen atmosphere, N-bromosuccinimide (132 mg, 0.743 mmol) was added to a solution of compound 1-3 (238 mg, 0.675 mmol) in acetonitrile (10 mL). The reaction system was stirred at room temperature for 3 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 1-4 (212 mg, yield: 72.9%). LC-MS (ESI) [M+H]+374.9 / 376.9.

[0212] Step 4: Preparation of compound 1-5

[0213] Under an ice-cold water bath and a nitrogen atmosphere, N-[2-chloro-4(trifluoromethyl)phenyl]-2-iodoacetamide (202 mg, 0.556 mmol) and N,N-diisopropylethylamine (120 mg, 0.927 mmol) were sequentially added to a solution of compound 1-4 (200 mg, 0.464 mmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred under an ice-cold water bath for 2 h. LCMS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1-5 (203 mg, yield: 65.7%). LC-MS (ESI) [M+H-56]+609.9 / 611.9.

[0214] Step 5: Preparation of compound 1-6

[0215] Compound 1-5 (467 mg, 0.700 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Petition 870250086442, dated 24 / 09 / 2025, page 116 / 530 55 / 114 3,6-dihydro-2H-pyran (177 mg, 0.840 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (14.0 mg, 0.070 mmol), and sodium carbonate (223 mg, 2.10 mmol) were dissolved in 1,4-dioxane / water (10 / 1 mL). The reaction system was stirred at 80°C for 4 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1-6 (303 mg, yield: 70.5%). LC-MS (ESI) [M+H]+670.2.

[0216] Step 6: Preparation of compound 1-7

[0217] At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 1-6 (118 mg, 176 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 1-7 (120 mg). The crude product was used directly in the next step. LC-MS (ESI) [M+H]+570.4.

[0218] Step 7: Preparation of compound 1-8

[0219] At room temperature, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.5 mg, 211 μmol) was added to a solution of the crude product of compound 1-7 (120 mg), 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (51.5 mg, 211 μmol) and N,N-diisopropylethylamine (68.1 mg, 527 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 4 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 1-8 (120 mg, total yield in two steps: 85.6%). LC-MS (ESI) [M+H]+796.2.

[0220] Step 8: Preparation of compound 1

[0221] Under an ice-water bath and a nitrogen atmosphere, a solution of boron trichloride in dichloromethane (1.00 mol / L, 251 pL, 251 μmol) was added dropwise to a solution of compound 1-8 (100 mg, 126 pmol) in dichloromethane (5 mL). The system of Petition 870250086442, dated 09 / 24 / 2025, page 117 / 530 56 / 114 reaction was stirred at room temperature for 3 h. LC-MS showed that the reaction was complete. Water (10 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 1 (36.0 mg, yield: 40.6%). LC-MS (ESI) [M+H]+706.2.

[0222] 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.18 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 9.0, 2.1 Hz, 1H), 6.64 (dd, J = 3.1, 1.6 Hz, 1H), 5.09 (s, 1H), 4.96 (d, J = 5.1 Hz, 2H), 4.63 (d, J = 12.8 Hz, 1H), 4.25 (d, J = 2.9 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 13.2 Hz, 1H), 3.16 (t, J = 12.9 Hz, 1H), 2.89 (s, 1H), 2.55 (s, 4H), 2.43 (s, 3H), 1.73 (d, J = 12.0 Hz, 1H), 1.56 (d, J = 11.9 Hz, 1H).

[0223] Exemplo 2: Síntese do composto 2

[0224] Etapa 1: Preparação do composto 2-2

[0225] Compound 2-1 (800 mg, 1.86 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)3,6-dihydro-2H-pyran (469 mg, 2.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (136 mg, 186 μmol) and cesium carbonate (1.82 g, 5.58 mmol) were dissolved in 1,4-dioxane / water (30 / 5 mL). The reaction system was stirred at 100°C for 12 h. LCMS showed that the reaction was complete. The reaction system was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by chromatography on Petition 870250086442, dated 09 / 24 / 2025, page 118 / 530 57 / 114 column (dichloromethane / methanol = 20 / 1) to obtain compound 2-2 (750 mg, yield: 93.1%). LC-MS (ESI) [M+H]+378.0.

[0226] Step 2: Preparation of compound 2-3

[0227] Under a nitrogen atmosphere, N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (629 mg, 1.73 mmol) and N,N-diisopropylethylamine (448 mg, 3.46 mmol) were sequentially added to a solution of compound 2-2 (750 mg, 1.73 mmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred at 40°C for 4 h. LCMS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-3 (770 mg, yield: 66.5%). LCMS (ESI) [M+H-56]+612.8.

[0228] Step 3: Preparation of compound 2-4

[0229] At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 2-3 (400 mg, 598 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 2-4 (340 mg). The crude product was used directly in the next step. LC-MS (ESI) [M+H]+569.0.

[0230] Step 4: Preparation of compound 2-5

[0231] At room temperature, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (232 mg, 717 μmol) was added to a solution of the crude product of compound 2-4 (340 mg), 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (175 mg, 717 μmol) and N,N-diisopropylethylamine (312 μL, 1.79 mmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 2-5 (450 mg, total yield in two steps: 94.7%). LC-MS (ESI) [M+H]+795.2. Petition 870250086442, dated 09 / 24 / 2025, page 119 / 530 58 / 114

[0232] Step 5: Preparation of compound 2

[0233] Under an ice-cold water bath and a nitrogen atmosphere, a boron trichloride solution in dichloromethane (1.00 mol / L, 880 μL, 880 μmol) was added dropwise to a solution of compound 2-5 (350 mg, 440 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 3 h. LCMS showed that the reaction was complete. Water (10 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 2 (85.0 mg, yield: 27.4%). LC-MS (ESI) [M+H]+705.0.

[0234] 1H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J = 17.6 Hz, 2H), 8.56 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.46 (s, 1H), 6.52 (s, 1H), 5.04 (d, J = 17.4 Hz, 3H), 4.62 (d, J = 12.8 Hz, 1H), 4.24 (d, J = 3.2 Hz, 2H), 3.81 (t, J = 5.4Hz, 2H), 3.55 (d, J = 13.2 Hz, 1H), 3.13 (t, J = 12.9 Hz, 1H), 2.86 (t, J = 12.9 Hz, 1H), 2.62 - 2.53 (m, 2H), 2.48 - 2.44 (m, 2H), 2.43 (s, 3H), 1.72 (d, J = 11.9 Hz, 1H), 1.55 (d, J = 12.1 Hz, 1H).

[0235] Example 3: Synthesis of compound 3

[0236] Step 1: Preparation of compound 3-2

[0237] Compound 3-1 (2.50 g, 13.5 mmol) and triphosgene (1.40 g, 4.72 mmol) were dissolved in dichloromethane (25 mL). Under an ice water bath and a nitrogen atmosphere, triethylamine (4.10 g, 40.5 mmol) was added dropwise to the reaction system. Petition 870250086442, dated 09 / 24 / 2025, pp. 120 / 530 59 / 114 After the dropwise addition was complete, the reaction system was stirred under an ice water bath for 1 h. Then, 4-amino-1-tert-butoxycarbonylpiperidine (2.52 g, 12.58 mmol) was added. The mixture was naturally heated to room temperature and reacted for 4 h. LC-MS showed that the reaction was complete. Water (100 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (70 mL x 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3-2 (2.60 g, yield: 51.7%). LC-MS (ESI) [M+H-56]+356.2.

[0238] Step 2: Preparation of compound 3-3

[0239] Under a nitrogen atmosphere, potassium tert-butoxide (2.13 g, 18.9 mmol) was added to a solution of compound 3-2 (2.60 g, 6.32 mmol) in ultradry tetrahydrofuran (30 mL). The reaction system was stirred at 60°C for 6 h. LCMS showed that the reaction was complete. Water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-3 (1.10 g, yield: 47.6%). LC-MS (ESI) [M+H-56]+310.4.

[0240] Step 3: Preparation of compound 3-4

[0241] Under an ice-cold water bath and a nitrogen atmosphere, N-bromosuccinimide (487 mg, 2.74 mmol) was added to a solution of compound 3-3 (1.00 g, 2.74 mmol) in dichloromethane (20 mL). The reaction system was stirred under an ice-cold water bath for 1 h. LCMS showed that the reaction was complete. Water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-4 (950 mg, yield: 78.1%). LC-MS (ESI) [M+H-56]+388.0 / 390.0.

[0242] Step 4: Preparation of compound 3-5 Petition 870250086442, dated 09 / 24 / 2025, page 121 / 530 60 / 114

[0243] Compound 3-4 (900 mg, 2.03 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)3,6-dihydro-2H-pyran (511 mg, 2.43 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (148 mg, 202 μmol) and cesium carbonate (1.98 g, 6.08 mmol) were dissolved in 1,4-dioxane / water (10 / 3 mL). The reaction system was stirred at 100°C for 12 h. LCMS showed that the reaction was complete. The reaction system was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-5 (300 mg, yield: 33.1%). LC-MS (ESI) [M+H-56]+392.2.

[0244] Step 5: Preparation of compound 3-6

[0245] Under an ice water bath and a nitrogen atmosphere, N-[2-chloro-4(trifluoromethyl)phenyl]-2-iodoacetamide (211 mg, 581 μmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol) were sequentially added to a solution of compound 3-5 (260 mg, 581 μmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred at 40°C for 3 h. LCMS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-6 (250 mg, yield: 63.0%). LC-MS (ESI) [M+H-56]+627.2.

[0246] Step 6: Preparation of compound 3-7

[0247] At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 3-6 (250 mg, 366 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 3-7 (250 mg). The crude product was used directly in the next step. LC-MS (ESI) [M+H]+583.2.

[0248] Step 7: Preparation of compound 3-8 Petition 870250086442, dated 09 / 24 / 2025, page 122 / 530 61 / 114

[0249] At room temperature, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (162 mg, 429 μmol) was added to a solution of the crude product of compound 3-7 (250 mg), 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (105 mg, 429 μmol) and N,N-diisopropylethylamine (55.4 mg, 429 pmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 12 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 3-8 (200 mg, total yield in two steps: 67.6%). LC-MS (ESI) [M+H]+ 809.4.

[0250] Step 8: Preparation of compound 3

[0251] Under an ice-cold water bath and a nitrogen atmosphere, a boron trichloride solution in dichloromethane (1.00 mol / L, 247 μL, 247 μmol) was added dropwise to a solution of compound 3-8 (100 mg, 123 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. Water (20 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 3 (13.6 mg, yield: 15.3%). LC-MS (ESI) [M+H]+719.2.

[0252] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.18 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.8, 2.1 Hz, 1H), 6.04 - 5.92 (m, 1H), 5.06 (s, 1H), 4.88 (d, J = 3.6 Hz, 2H), 4.63 (d, J = 12.9 Hz, 1H), 4.21 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 13.3 Hz, 1H), 3.13 (t, J = 12.9 Hz, 1H), 2.86 (t, J = 12.7 Hz, 1H), 2.59 (d, J = 13.6 Hz, 1H), 2.45 (s, 3H), 2.43 (s, 3H), 2.36 - 2.30 (m, 3H), 1.70 (d, J = 12.0 Hz, 1H), 1.53 (d, J = 12.0 Hz, 1H).

[0253] Example 4: Synthesis of compound 4 Petition 870250086442, dated 09 / 24 / 2025, p. 123 / 530 62 / 114 4-6

[0254] Step 1: Preparation of compound 4-2

[0255] Starting material 4-1 (3.80 g, 33.31 mmol) and PMBCl (7.85 g, 49.97 mmol) were dissolved in DMF (40.0 mL) and potassium carbonate (6.90 g, 49.97 mmol) was added at room temperature. The reaction system was stirred at 60°C for 5 h and then cooled. Water (50 mL) was added to quench the reaction, followed by the addition of a mixed solvent of petroleum ether and ethyl acetate (40 mL, 5:1). After stirring for 5 min, the mixture was filtered. The filter cake was washed with a mixed solvent of petroleum ether and ethyl acetate (5:1) to obtain compound 4-2 (3.90 g) with a yield of 50%.

[0256] Step 2: Preparation of compound 4-3

[0257] Compound 4-2 (3.40 g, 14.52 mmol) was dissolved in a mixed solvent of methanol and water (40 mL, 3:1). Iron powder (2.44 g, 43.55 mmol) and ammonium chloride (3.92 g, 72.58 mmol) were then added. The reaction system was stirred at 70°C for 2 h and then cooled. The suspension was filtered through diatomaceous earth and the filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with saturated brine, separated and dried. The solvent was removed using a rotary evaporator to obtain compound 4-3 (2.55 g) with a yield of 86.0%. LC-MS(ESI)[M+H]+: 205.2. Petition 870250086442, dated 09 / 24 / 2025, page 124 / 530 63 / 114

[0258] Step 3: Preparation of compound 4-4

[0259] Compound 4-3 (2 g, 9.79 mmol), tert-butyl 4-(1-methoxy-1,3-dioxolan-2-yl)piperazine 1-carboxylate (3.5 g, 11.13 mmol) and TsOH (168.44 mg, 979.30 μmol) were dissolved in EtOH (35 mL). After the addition was complete, the system was heated to 100°C and stirred for 12 h. TLC showed the disappearance of the starting material. The reaction system was quenched directly with water and the product was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium carbonate, separated, dried, and then concentrated to dryness under vacuum to obtain compound 4-4 (4.91 g). The residue was used directly in the next step. The yield of the crude product was 100%. LC-MS(ESI)[M+H]+: 501.2.

[0260] Step 4: Preparation of compound 4-5

[0261] Compound 4-4 (4 g, 7.99 mmol) was dissolved in diphenyl ether:dichloromethane (5 mL, 4:1) and the solution was added slowly dropwise to diphenyl ether (43 mL) that had been preheated to an internal temperature of 220°C. After the addition was complete, the system was stirred at 220°C for 4.5 min. After the system was cooled to room temperature, the reaction was quenched directly with cyclohexane. The solid was filtered and washed with cyclohexane to obtain compound 4-5 (1.1 g) with a yield of 29.4%. LC-MS (ESI) [M+H]+: 469.2.

[0262] Step 5: Preparation of compound 4-6

[0263] Compound 4-5 (1 g, 2.13 mmol) was dissolved in DMF (7 mL) and ethyl bromoacetate (712.84 mg, 4.27 mmol) and cesium carbonate (2.10 g, 6.40 mmol) were added to it. After the addition was complete, the system was stirred at room temperature for 2 h. The reaction system was quenched directly with water and the product was extracted with ethyl acetate. The organic phase was separated, dried, and concentrated to dryness under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-6 (0.27 g) with a yield of 22.9%. LC-MS (ESI) [M+H]+: 555.2.

[0264] Step 6: Preparation of compound 4-7

[0265] Compound 4-6 (170 mg, 306.51 μmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added to it at room temperature. After the addition was complete, the system was stirred at room temperature for 0.5 h. The disappearance of the starting material Petition 870250086442, dated 09 / 24 / 2025, page 125 / 530 64 / 114 was detected by TLC. The system was concentrated directly to dryness under vacuum. The residue was used directly in the next step and the yield of the crude product was 100%. LCMS(ESI)[M+H]+:455.2.

[0266] Step 7: Preparation of compound 4-8

[0267] Compound 4-7 (150 mg, 330.02 μmol) was dissolved in TFA (2 mL) and TfOH (0.05 mL) was added to it. After the addition was complete, the system was stirred at room temperature for 10 min. The disappearance of the starting material was detected by TLC. The system was concentrated directly to dryness under vacuum. The residue was used directly in the next step and the yield of the crude product was 100%. LCMS(ESI)[M+H]+: 335.2.

[0268] Step 8: Preparation of compound 4-9

[0269] Compound 4-8 (200 mg, 598.13 μmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (146.09 mg, 598.13 μmol) were dissolved in DMF (3.96 mL) and DIEA (773.05 mg, 5.98 mmol, 1.04 mL) and HATU (293.36 mg, 777.58 μmol) were added to the same. After the addition was complete, the system was stirred at room temperature for 2 h. The reaction system was quenched directly with water and the byproducts were extracted with ethyl acetate. The aqueous phase was washed with citric acid and extracted with ethyl acetate, then the organic phase was separated, dried and concentrated to dryness under vacuum. The residue was purified by preparative HPLC to obtain compound 4-9 (110 mg) with a yield of 32.83%. LC-MS (ESI) [M+H]+: 561.2.

[0270] Step 9: Preparation of compound 4-10

[0271] Compound 4-9 (16 mg, 28.54 μmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (12.78 mg, 99.89 μmol) and PhenCuPPh3Br (6.70 mg, 11.42 μmol) were dissolved in DMSO (1 mL). After the addition was complete, the system was heated to 90°C under air balloon protection and stirred for 3 h. The reaction system was quenched directly with water and the product was extracted with ethyl acetate. The organic phase was separated, dried and concentrated to dryness under vacuum. The residue was purified by medium pressure preparative column (DCM:MeOH = 10:1) to obtain compound 4-10 (11 mg) with a yield of 59.88%. LC-MS (ESI) [M+H]+: 643.2. Petition 870250086442, dated 09 / 24 / 2025, page 126 / 530 65 / 114

[0272] Step 10: Preparation of compound 4-11

[0273] Compound 4-10 (17 mg, 26.45 μmol) was dissolved in a mixed solvent of water (1.5 mL), MeOH (1.5 mL), and THF (1.5 mL), then NaOH (10.58 mg, 264.51 μmol) was added. After the addition was complete, the system was stirred at room temperature for 0.25 h. The pH was adjusted to 4.0 with 3N hydrochloric acid, and ethyl acetate was added to extract the product. The organic phase was separated, dried, and subjected to rotary evaporation to obtain crude product 4-11 (16 mg) with a crude product yield of 100%. LC-MS (ESI) [M+H]+: 615.2.

[0274] Step 11: Preparation of compound 4-12

[0275] Compound 4-11 (16 mg, 26.05 μmol), 2-chloro-4-trifluoromethylaniline (15.20 mg, 78.17 μmol), and pyridine (20.37 mg, 261 μmol) were dissolved in DCM (0.5 mL), then phosphorus oxychloride (20.29 mg, 130 μmol) was added. After the addition was complete, the system was stirred at room temperature for 0.5 h. TLC showed a product point. The reaction system was quenched directly with water, and the product was extracted with ethyl acetate. The organic phase was separated, dried, and concentrated to dryness under vacuum. The residue was purified by medium-pressure preparative column (dichloromethane:methanol = 10:1) to obtain compound 4-12 (16 mg) with a yield of 77.88%. LC-MS (ESI) [M+H]+: 792.2.

[0276] Step 12: Preparation of compound 4

[0277] Compound 4-12 (18 mg, 22.75 μmol) was dissolved in DCM (2 mL), then boron trichloride (180.00 μL, 1N) was added at room temperature. After the addition was complete, the system was stirred at room temperature for 0.25 h. The reaction system was quenched directly with methanol and the residue was purified by preparative HPLC to obtain the crude product of compound 4 (10.63 mg, containing isomers). Crude product 4 was further purified by SFC (column: ChiralPak AD, 250 χ 30 mm ID, 10 μm; mobile phase [A: carbon dioxide, B: isopropanol (containing 0.1% water with ammonia)]; B% composition: 40%, flow rate: 150 mL / min, column temperature: 38°C, wavelength: 220 nm, cycle time: approximately 5 min) to obtain compound 4 (4.11 mg), with a yield of 38.66% (target product retention time: 0.788 min; analytical method: column: ChiralPak AD, 50 χ Petition 870250086442, dated 09 / 24 / 2025, page 127 / 530 66 / 114 4.6 mm ID, 3 μm; mobile phase [A: carbon dioxide, B: isopropanol (containing 0.05% DEA)]; 40% B, flow rate: 3 mL / min, column temperature: 35°C). LC-MS (ESI) [M+H]+: 702.2.

[0278] 1HNMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.55-7.47 (m, 1H), 6.79 — 6.73 (m, 1H), 5.29 (s, 2H), 4.30-4.22 (m, 2H), 3.94-3.85 (m, 2H), 3.84-3.72 (m, 2H), 3.42 — 3.28 (m, 1H), 3.10 — 2.95 (m, 3H), 2.81 (s, 3H), 2.712.60 (m, 1H), 2.38 (s, 3H), 2.09 (t, J = 7.6 Hz, 1H), 1.99-1.87 (m, 1H), 0.80 (t, J = 6.4 Hz, 3H).

[0279] Example 5: Synthesis of compound 5

[0280] Step 1: Synthesis of compound 5-2

[0281] A solution of compound 5-1 (1.0 g, 8.84 mmol) in THF (30 mL) was added dropwise to a solution of NaH (1.06 g, 26.54 mmol, 60% purity) in THF (30 mL) at 0°C, stirred at 0°C for 0.5 h, followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.77 g, 10.62 mmol, 1.88 mL). The mixture was reacted at 0°C for a further 1.5 h. The mixture was slowly added to a saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-2 (2.1 g, 8.63 mmol) with a yield of 97.58%.

[0282] Step 2: Synthesis of compound 5-3 Petition 870250086442, dated 09 / 24 / 2025, page 128 / 530 67 / 114

[0283] Compound 5-2 (1.0 g, 4.11 mmol) was dissolved in MeOH (10 mL) and Pd / C (200 mg, 10% purity) was added. The mixture was reacted under a hydrogen atmosphere at 25°C for 4 h until the starting material was completely consumed. The mixture was filtered and then concentrated by rotary evaporation under reduced pressure to obtain compound 5-3 (870 mg, 4.08 mmol) with a yield of 99.2%. LC-MS (ESI) [M+H]+: 214.2.

[0284] Step 3: Synthesis of compound 5-4

[0285] Compound 5-3 (1.0 g, 4.69 mmol) and tert-butyl 4-(1-methoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate (1.47 g, 4.69 mmol) were dissolved in toluene (10 mL). p-Toluenesulfonic acid (80.71 mg, 468.71 μmol) was added and the mixture was reacted at 120°C for 16 h until the starting material was completely consumed. The mixture was poured into a saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-4 (1.28 g) with a yield of 53.58%. LC-MS (ESI) [M+H]+:510.4.

[0286] Step 4: Synthesis of compound 5-5

[0287] Diphenyl ether (8 mL) was heated to 280°C and compound 5-4 (680 mg, 1.33 mmol) was added under reflux. The reaction was carried out for 5 min until the product was formed. The mixture was cooled to room temperature, then poured into cyclohexane, stirred and then filtered. The filtrate was concentrated and then both the filtrate and the filter cake were separately subjected to column chromatography (PE / EA = 10 / 1) to obtain compound 5-5 (100 mg) with a yield of 15.69%. LC-MS (ESI) [M+H]+:478.4.

[0288] Step 5: Synthesis of compound 5-6

[0289] Compound 5-5 (160 mg, 334.96 μmol) was dissolved in ACN (3 mL), followed by the addition of cesium carbonate (327.41 mg, 1.00 mmol) and ethyl bromoacetate (83.91 mg, 502.44 μmol). The mixture was reacted at 25°C for 1 h until the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 56 (83 mg) with a yield of 43.9%. LC-MS (ESI) [M+H]+:564.4. Petition 870250086442, dated 09 / 24 / 2025, page 129 / 530 68 / 114

[0290] Step 6: Synthesis of compound 5-7

[0291] Compound 5-6 (30 mg, 53.21 μmol) was dissolved in MeOH (3 mL), followed by the addition of HCl (4 M, 4.00 mmol, 1 mL). The mixture was reacted at 25°C for 4 h until the starting material was completely consumed. The mixture was poured into a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-7 (24 mg) with a yield of 97.3%. LC-MS (ESI) [M+H]+: 464.3.

[0292] Step 7: Synthesis of compound 5-8

[0293] Compound 5-7 (177.00 mg, 724.69 μmol) was dissolved in DMF (5 mL), followed by the addition of HATU (455.67 mg, 1.21 mmol), DIEA (234.15 mg, 1.81 mmol, 315.57 μL) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid compound (280 mg, 603.91 μmol). The resulting mixture was reacted at 25°C for 2 h until the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain compound 5-8 (360 mg) with a yield of 86.4%. LCMS (ESI) [M+H]+: 690.2.

[0294] Step 8: Synthesis of compound 5-9

[0295] Compound 5-8 (350 mg, 507.34 μmol) was dissolved in a solution of HCl (4 M, 24.00 mmol, 6 mL) in dioxane (6 mL). The reaction was carried out at 25°C for 4 h until the starting material was completely consumed. The reaction mixture was poured into a saturated sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 5-9 (200 mg) with a yield of 70.4%. LC-MS (ESI) [M+H]+: 690.2.

[0296] Step 9: Synthesis of compound 5-10

[0297] Compound 5-9 (300 mg, 536.08 μmol) was dissolved in DMSO (1 mL) and (3,6-dihydro-2H-pyran-4-yl)boronic acid (102.87 mg, 804.12 μmol) and PhenCuPPh (30.45 mg, 53.61 μmol) were added. The resulting reaction system was stirred under air until Petition 870250086442, dated 09 / 24 / 2025, page 130 / 530 69 / 114 reaction complete. The reaction mixture was quenched with water and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 3%) to obtain compound 5-10 (135 mg, 204.06 μmol) with a yield of 38.1%. LC-MS (ESI) [M+H]+: 642.2.

[0298] Step 10: Synthesis of compound 5-11

[0299] Compound 5-10 (130.00 mg, 202.58 μmol) was dissolved in MeOH (0.5 mL), THF (1.5 mL), and water (0.5 mL). LiOH (16.98 mg, 709.04 μmol) was added. The resulting mixture was reacted at 25°C for 1 h until the starting material was completely consumed. The mixture was adjusted to pH < 4 with hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-11 (120 mg, 195.55 μmol) with a yield of 96.53%. LC-MS (ESI) [M+H]+: 612.2.

[0300] Step 11: Synthesis of compound 5-12

[0301] Compound 5-11 (110.00 mg, 179.25 pmol), 2-chloro-4-trifluoromethylaniline (52.58 mg, 268.88 μmol) and pyridine (70.89 mg, 896.26 pmol, 72.20 μL) were dissolved in DCM (1.93 mL). Phosphorus oxychloride (41.23 mg, 268.88 pmol) was added. The resulting reaction mixture was stirred at 25°C for 1 h until the starting material was completely consumed. Water (5 mL) was added to quench the reaction and the product was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. The crude product was separated by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 5-12 (130 mg, 164.30 pmol) with a yield of 91.66%. LC-MS (ESI) [M+H]+: 791.2.

[0302] Step 12: Synthesis of compound 5

[0303] Compound 5-12 (60 mg, 75.83 pmol) was dissolved in DCM (2 mL) and boron trichloride (88.85 mg, 758.33 pmol) was added. The mixture was reacted at 25°C for 0.5 h until the starting material was completely consumed. The mixture was separated by preparative HPLC to obtain compound 5 (5 mg, 7.13 pmol) with a yield of 9.40%. LC-MS Petition 870250086442, dated 09 / 24 / 2025, p. 131 / 530 70 / 114 (ESI) [M+H]+: 701,2.

[0304] 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 10.20 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 5.16 (s, 2H), 4.49 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 3.0 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.73 (q, J = 13.1 Hz, 2H), 3.46 (d, J = 12.5 Hz, 1H), 3.19 (t, J = 12.3 Hz, 1H), 2.93 (t, J = 12.2 Hz, 3H), 2.71 (s, 3H), 2.44 (s, 3H), 2.00 (q, J = 6.9, 6.3 Hz, 1H), 1.17 (t, J = 7.4 Hz, 3H).

[0305] Example 6: Synthesis of compound 6

[0306] Step 1: Preparation of compound 6-1

[0307] Intermediate 5-7 (160 mg, 345.83 μmol) and 3-(benzyloxy)picolinic acid (87.20 mg, 380.41 μmol) were dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (157.79 mg, 414.99 μmol) and N,N-diisopropylethylamine (134.09 mg, 1.04 mmol, 180.71 μL) were added sequentially. After the addition was complete, the resulting reaction system was stirred at 25°C for 1 h. LC-MS showed the completion of the reaction. The reaction mixture was concentrated directly under reduced pressure and the resulting residue was purified by silica gel column (DCM / MeOH = 5%) to obtain compound 6-1 (210 mg) with a yield of 90.11%. LC-MS (ESI) [M+H]+: 675.2.

[0308] Step 2: Preparation of compound 6-2

[0309] Compound 6-1 (210.31 mg, 311.63 μmol) was dissolved in a dioxane HCl solution (4 M, 4.00 mmol, 1 mL). The resulting reaction system was stirred at 25°C for 1 Petition 870250086442, dated 09 / 24 / 2025, page 132 / 530 71 / 114 h. LC-MS showed the completion of the reaction. The reaction mixture was cooled to 25°C and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 6-2 (150 mg) with a yield of 75.13%. LC-MS (ESI) [M+H]+: 545.2.

[0310] Step 3: Preparation of compound 6-3

[0311] Compound 6-2 (67 mg, 123.03 μmol) was dissolved in dimethyl sulfoxide (0.5 mL). 3,6-Dihydro-2H-pyran-4-boronic acid (23.61 mg, 184.54 μmol) and PhenCuPPhBr2 (3.49 mg, 6.15 μmol) were added. The resulting reaction mixture was stirred under air for approximately 12 h until the starting material was completely consumed. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column (MeOH / DCM = 3%) to obtain compound 6-3 (43 mg) with a yield of 52.98%. LC-MS (ESI) [M+H]+: 627.2.

[0312] Step 4: Preparation of compound 6-4

[0313] Compound 6-3 (41 mg, 62.15 μmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). A solution of lithium hydroxide (4.47 mg, 186.45 μmol) in water (0.2 mL) was added. After the addition was complete, the resulting reaction system was stirred at room temperature for 5 h until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The remaining aqueous phase was adjusted to neutral pH with dilute 1 M hydrochloric acid and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 6-4 (35 mg), which was used directly in the next step. The crude product yield was 83.72%. LC-MS (ESI) [M+H]+: 599.2.

[0314] Step 5: Preparation of compound 6-5

[0315] Intermediate 6-4 (25 mg, 37.17 μmol), 3-chloro-4-aminobenzotrifluoride (10.90 mg, 55.75 μmol) and pyridine (14.70 mg, 185.84 μmol, 14.97 μL) were dissolved in dichloromethane. Petition 870250086442, dated 09 / 24 / 2025, page 133 / 530 72 / 114 (0.5 mL). Phosphorus oxychloride (17.10 mg, 111.50 μmol) was added. After the addition was complete, the resulting reaction system was stirred at 25°C for 2 h until the reaction was complete. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column (DCM / MeOH = 50:1) to obtain compound 6-5 (23 mg) with a yield of 70.64%. LC-MS (ESI) [M+H]+: 776.4.

[0316] Step 6: Preparation of compound 6

[0317] Intermediate 6-5 (25 mg, 28.54 pmol) was dissolved in dichloromethane (0.5 mL) and boron trichloride (16.72 mg, 142.68 pmol) was added. After the addition was complete, the resulting reaction system was stirred at 25°C for 1 h. LC-MS showed the completion of the reaction. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 6 (2.16 mg) with a yield of 11.03%. LC-MS (ESI) [M+H]+: 686.2.

[0318] 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.63 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 3.8 Hz, 2H), 6.41 (s, 1H), 5.16 (s, 2H), 4.52 (d, J = 12.3 Hz, 1H), 4.28 (d, J = 2.9 Hz, 2H), 3.89 (t, J = 5.4 Hz, 2H), 3.73 (t, J = 14.6 Hz, 2H), 3.18 (q, J = 12.7 Hz, 3H), 2.91 (q, J = 12.0, 9.3 Hz, 3H), 2.71 (tt, J = 6.6, 2.9 Hz, 4H), 1.17 (t, J = 7.4 Hz, 3H).

[0319] Example 7: Synthesis of compound 7 Petition 870250086442, dated 09 / 24 / 2025, page 134 / 530 73 / 114

[0320] Step 1: Preparation of compound 7-2

[0321] At room temperature, compound 7-1 (23 g, 150 mmol) was dissolved in dimethyl sulfoxide (200 mL) and sodium methoxide (135 g, 750 mmol) was added. Under a nitrogen atmosphere, the reaction system was stirred at 120°C for 16 h. Water was added and the mixture was extracted several times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was suspended with pure ethyl acetate to obtain target compound 7-2 (11.9 g) with a yield of 43.28%. LC-MS (ESI) [M+H]+: 150.1.

[0322] Step 2: Preparation of compound 7-3

[0323] At room temperature, intermediate 7-2 (11.9 g, 80 mmol) was dissolved in N-methylpyrrolidone (240 mL), followed by the addition of m-chloroperoxybenzoic acid (32 g, 184 mmol). The reaction was carried out at room temperature for 16 h until the reaction was complete. Methyl tert-butyl ether solution (60 mL) was added and, after stirring for 10 min, the liquid was removed by filtration. The filter cake was rinsed with ethyl acetate and collected. The filter cake was dissolved in methyl tert-butyl ether solution (200 mL) and stirred. Petition 870250086442, dated 09 / 24 / 2025, page 135 / 530 74 / 114 for 30 min and then the liquid was removed by filtration. The solid obtained after filtration was dried to obtain compound 7-3 (11.9 g) with a 100% yield. LC-MS (ESI) [M+H]+: 166.1.

[0324] Step 3: Preparation of compound 7-4

[0325] At room temperature, intermediate 7-3 (10.9 g, 66 mmol) was dissolved in phosphorus oxychloride (100 mL) and the reaction was carried out at 50°C for 16 h until the reaction was complete. The solvent was subjected to rotary evaporation to dryness. Under an ice bath, the solution was adjusted to alkaline with sodium hydroxide and extracted several times with ethyl acetate and water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-4 (11.0 g) with a yield of 90.78%. LC-MS (ESI) [M+H]+: 183.9.

[0326] Step 4: Preparation of compound 7-5

[0327] At room temperature, intermediate 7-4 (11 g, 60 mmol) was dissolved in tetrahydrofuran (110 mL), followed by the addition of 3,4-dihydro-2H-pyran (7.6 g, 90 mmol) and p-toluenesulfonic acid monohydrate (1.1 g, 6 mmol). The resulting reaction mixture was reacted at room temperature for 16 h until the reaction was complete, diluted with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-5 (14.8 g) with a yield of 92.27%. LC-MS(ESI) [M+H]+:267.9.

[0328] Step 5: Preparation of compound 7-6

[0329] At room temperature, intermediate 7-5 (14 g, 52 mmol) and vinylboronic acid pinacol ester (12 g, 78 mmol) were dissolved in a mixed solution of 1,4-dioxane (70 mL) and water (35 mL), followed by the addition of methanesulfonate(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.3 g, 1.56 mmol) and cesium fluoride (20 g, 130 mmol). The system was purged with nitrogen and the reaction mixture was stirred and reacted at 110°C for 16 h. LC-MS showed completion of the reaction. The mixture of Petition 870250086442, dated 09 / 24 / 2025, p. 136 / 530 75 / 114 reaction was diluted with water (50 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 7-6 (13.2 g) with a yield of 98%. LC-MS (ESI) [M+H]+: 260.0.

[0330] Step 6: Preparation of compound 7-7

[0331] At room temperature, intermediate 7-6 (13.2 g, 51 mmol) was dissolved in methanol (130 mL) and 10% palladium was added over a carbon catalyst (5 g). The reaction was stirred under a hydrogen atmosphere at room temperature for 16 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-7 (10.9 g) with a yield of 81.9%. LC-MS(ESI) [M+H]+: 262.1.

[0332] Step 7: Preparation of compound 7-8

[0333] At room temperature, compound 7-7 (3 g, 11 mmol) was dissolved in acetonitrile (30 mL) and ethyl bromoacetate (19 g, 15 mmol) was added. The reaction was carried out at 70°C under a nitrogen atmosphere for 16 h until the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reversed-phase column chromatography (A: formic acid / water, B: acetonitrile) to obtain target compound 7-8 (1.2 g) with a yield of 31.20%. LC-MS(ESI) [M+H]+: 333.9.

[0334] Step 8: Preparation of compound 7-9

[0335] At room temperature, intermediate 7-8 (1.2 g, 3.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N-bromosuccinimide (0.6 g, 3.6 mmol). The reaction was carried out at room temperature for 16 h until the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / (methanol:dichloromethane = 1:1) = 10 / 1) to obtain target compound 7-9 (0.4 g) with a yield of 31.56%. LC-MS(ESI) Petition 870250086442, dated 09 / 24 / 2025, page 137 / 530 76 / 114 [M+H]+: 411.8.

[0336] Step 9: Preparation of compound 7-10

[0337] At room temperature, intermediate 7-9 (0.4 g, 1.1 mmol) and esterpinacol of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid (0.7 g, 2.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (2 mL), followed by the addition of chlorine(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.089 g, 0.1 mmol), potassium phosphate (0.7 g, 3.4 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.1 g, 0.3 mmol). After purging with nitrogen, the reaction mixture was stirred and reacted at 100°C for 16 h until the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (silica, dichloromethane / methanol = 10 / 1) to obtain the target compound 7-10 (0.3 g) with a yield of 57.8%. LC-MS (ESI) [M+H]+: 515.0.

[0338] Step 10: Preparation of compound 7-11

[0339] At room temperature, compound 7-10 (0.3 g, 0.6 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and ethanol (2 mL). Raney nickel catalyst (0.5 g) was added and the system was purged with hydrogen. The reaction was carried out at room temperature for 16 h until the reaction was complete. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-11 (0.15 g) with a yield of 49.80%. LC-MS(ESI) [M+H]+: 417.9.

[0340] Step 11: Preparation of compound 7-12

[0341] At room temperature, intermediate 7-11 (0.15 g, 0.29 mmol) was dissolved in tetrahydrofuran (6 mL), followed by the addition of a dioxane hydrochloride solution (2 mL, 1 mol / L). The reaction was carried out at room temperature for 16 h until the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure to obtain compound 7-12 (0.15 g) with a 100% yield. LC-MS(ESI) [M+H]+: 333.1.

[0342] Step 12: Preparation of compound 7-13 Petition 870250086442, dated 09 / 24 / 2025, page 138 / 530 77 / 114

[0343] At room temperature, intermediate 7-12 (0.13 g, 0.25 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), followed by the addition of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (0.067 g, 0.27 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (0.14 g, 0.37 mmol), and N,N-diisopropylethylamine (0.16 g, 1.26 mmol). The reaction was carried out at room temperature for 16 h until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 7-13 (0.10 g) with a yield of 47.14%. LC-MS(ESI) [M+H]+:559.2.

[0344] Step 13: Preparation of compound 7-14

[0345] At room temperature, intermediate 7-13 (0.083 g, 0.15 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of 3,6-dihydro-2H-pyran-4-boronic acid (0.019 g, 0.15 mmol), copper(II) acetate monohydrate (0.045 g, 0.22 mmol), and pyridine (0.047 g, 0.59 mmol). The reaction was carried out at room temperature for 16 h until the reaction was complete. The reaction mixture was cooled, diluted with water (10 mL), and extracted over dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-14 (0.076 g) with a yield of 79.83%. LC-MS (ESI) [M+H]+: 641.1.

[0346] Step 14: Preparation of compound 7-15

[0347] At room temperature, intermediate 7-14 (0.076 g, 0.12 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (1 mL), followed by the addition of lithium hydroxide (0.02 g, 0.47 mmol), and the reaction was carried out at room temperature for 16 h until the reaction was complete. The solvent was removed by rotary evaporation under reduced pressure. Water (10 mL) was added for dilution and the pH of the mixture was adjusted to <6 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL x 2). The phases Petition 870250086442, dated 09 / 24 / 2025, page 139 / 530 78 / 114 organic compounds were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was lyophilized under vacuum to obtain compound 7-15 (0.076 g) with a 100% yield. LC-MS (ESI) [M+H]+: 613.3.

[0348] Step 15: Preparation of compound 7-16

[0349] At room temperature, the intermediate 7-15 (0.056 g, 0.09 mmol), N,N,N',N-tetramethylchloroformamidinium hexafluorophosphate (0.030 g, 0.108 mmol), 1-methylimidazole (0.011 g, 0.135 mmol) and 3-chloro-4-aminobenzotrifluoride (0.017 g, 0.09 mmol) were dissolved in acetonitrile (3 mL). After the reaction was carried out at room temperature for 1 h, LC-MS showed the completion of the reaction. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-16 (0.092 g) with a 100% yield. LC-MS (ESI) [M+H]+: 789.9.

[0350] Step 16: Preparation of compound 7

[0351] At room temperature, compound 7-16 (0.09 g, 0.11 mmol) was dissolved in dichloromethane (5 mL) and boron trichloride (0.1 mL) was added. The reaction system was purged with nitrogen and the reaction was carried out at room temperature for 16 h until the reaction was complete. The reaction mixture was quenched with methanol (5 mL) and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to obtain compound 7 (24.75 mg) with a yield of 30.1%. LC-MS (ESI) [M+H]+: 700.2.

[0352] 1HNMR (400 MHz, MeOH-d4) δ 8.60-8.54 (m,1H), 8.42-8.33(m,1H), 8.218.15(m,1H), 7.82-7.76 (m, 1H), 7.66-7.58(m,1H), 6.59-6.48(m,1H), 5.38-5.31(m,2H), 4.854.78(m, 1H), 4.36-4.31(m,2H), 4.20-4.09(m,1H), 4.00-3.94(m, 2H), 3.31-3.22(m,1H), 3,112,79 (m, 6H), 2.77-2.72(m,2H), 2.55 -2.50(m,3H), 1.74-1.50(m,2H), 1.37-1.31(m,3H).

[0353] Example 8: Synthesis of compound 8 Petition 870250086442, dated 09 / 24 / 2025, page 140 / 530 79 / 114

[0354] Step 1: Preparation of compound 8-1

[0355] Compound 4-11 (21 mg, 34.17 μmol), 2-methyl-4-trifluoromethylaniline (17.95 mg, 102.50 μmol), and pyridine (27.03 mg, 341.66 μmol, 27.52 μL) were dissolved in DCM (1.5 mL). Phosphorus oxychloride (26.19 mg, 170.83 μmol) was added at room temperature. After the addition was complete, the system was stirred at room temperature for 1 h until the reaction was complete. The reaction mixture was quenched with water (5 mL) and the product was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM:MeOH = 19:1) to obtain compound 8-1 (26 mg) with a yield of 65.0%. LC-MS(ESI)[M+H]+: 772.3.

[0356] Step 2: Preparation of compound 8

[0357] Compound 8-1 (20 mg, 25.91 μmol) was dissolved in DCM (2 mL) and a boron trichloride solution in hexane (0.2 mL, 1 M) was added at room temperature. The mixture was stirred at room temperature for 1 h until the reaction was complete. The reaction mixture was quenched with methanol (5 mL) and the solvent was removed by rotary evaporation under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the crude product of compound 8 (12 mg, containing isomers). The crude product was further purified by preparative SFC (column: ChiralPak AD, 250 x 30 mm ID, 10 μm; mobile phase: A: CO2; B: isopropanol (0.1% NH3H2O); composition: B 40%; flow rate: 150 mL / min; back pressure: 100 bar; column temperature: 38°C; wavelength: 220 nm; cycle time: approximately 5 min) to obtain compound 8 (4.33 mg, yield: 24.5%). The analytical method for the target product was as follows: column: ChiralPak AD, 50 x 4.6 mm ID, 3 μm; mobile phase: A: CO2; B: isopropanol (0.05% DEA); composition: B 40%; flow rate: 3 mL / min; back pressure: 100 bar; column temperature: 35°C; wavelength: 220 nm;. Petition 870250086442, dated 09 / 24 / 2025, p. 141 / 530 80 / 114 LC-MS (ESI) [M+H]+: 682.3.

[0358] 1H NMR (400 MHz, MeOD-d4) δ 8.41 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.81 (s, 1H), 5.28 (s, 2H), 4.33 (s, 2H), 4.00-3.74 (m, 4H), 3.15 - 3.02 (m, 4H), 2.86 (s, 3H), 2.76-2.65 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 2.19-2.09 (m, 1H), 2.031.93(m, 1H), 0.84 (t, J = 6.8 Hz, 3H).

[0359] Example 9: Synthesis of compound 9 4-11

[0360] Step 1: Preparation of compound 9-1

[0361] Compound 4-11 (30 mg, 48.81 μmol), 2-fluoro-4-trifluoromethylaniline (34.97 mg, 195.23 μmol) and pyridine (38.61 mg, 488.08 μmol, 39.32 μL) were dissolved in dichloromethane (1 mL). Phosphorus oxychloride (37.42 mg, 244.04 μmol) was added at room temperature and the mixture was stirred at room temperature for 1 h until the reaction was complete. The reaction mixture was poured into water (5 mL) to quench the reaction, extracted with ethyl acetate (10 mL x 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by preparative silica gel column chromatography (DCM:MeOH = 19:1) to obtain compound 9-1 (27.7 mg) with a yield of 73.28%. LC-MS (ESI) [M+H]+: 776.2.

[0362] Step 2: Preparation of compound 9

[0363] Compound 9-1 (30 mg, 38.67 μmol) was dissolved in DCM (3 mL). A boron trichloride solution in n-hexane (0.3 mL, 1 M) was added at room temperature and the mixture was stirred at room temperature for 0.6 h until the reaction was complete. Methanol (5 mL) was then added to quench the reaction and the solvent was evaporated to dryness. The residue was purified by preparative HPLC to obtain the crude product of compound 9 (15 mg, containing isomers). The crude product was further purified by SFC (column: ChiralPak AD, 250 x 30 mm ID, 10 μm; mobile phase [A: carbon dioxide, B: ethanol (containing 0.1% of Petition 870250086442, dated 09 / 24 / 2025, page 142 / 530 81 / 114 water with ammonia)]; composition B%: 30%, flow rate: 150 mL / min, column temperature: 38°C, wavelength: 220 nm, cycle time: approximately 9 min) to obtain compound 9 (5.08 mg) with a yield of 33.8%. (The product peak retention time was 0.637 min. SFC analysis conditions: column: ChiralPak AD, 50 x 4.6 mm ID, 3 μm; mobile phase [A: carbon dioxide, B: ethanol (containing 0.05% DEA)]; 5-40% B, flow rate: 3 mL / min, column temperature: 35°C). LC-MS (ESI) [M+H]+: 686.2.

[0364] 1HNMR(400MHz, Methanol-d4) δ 8.42-8.20(m, 2H), 7.57(d, J =12.0Hz,1H), 7.47(d, J=8.4Hz,1H), 6.88-6.79(m, 1H), 5.34(s,2H), 4.36(s, 2H),4.09-3.81(m, 4H), 3.60-3.40(m, 1H), 3.22-3.06 (m, 3H), 2.89(s,3H), 2.84-2.68(m,1H), 2.47 (s,3H), 2.24-2.14(m,1H), 2.10 1.98(m,1H),1.33-L28 (m,3H).

[0365] Example 10: Synthesis of compound 10

[0366] Step 1: Preparation of compound 10-1

[0367] At room temperature, intermediate 7-10 (200 mg, 0.39 mmol) was dissolved in tetrahydrofuran (6 mL), followed by the addition of a dioxane hydrochloride solution (2 mL, 1 M). After the reaction was carried out at room temperature for 2 h, LC-MS showed the completion of the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain compound 10-1 (200 mg) with a 100% yield. LC-MS(ESI) [M+H]+: 331.1.

[0368] Step 2: Preparation of compound 10-2

[0369] At room temperature, intermediate 10-1 (200 mg, 0.39 mmol) was dissolved in Petition 870250086442, dated 09 / 24 / 2025, page 143 / 530 82 / 114 N,N-dimethylformamide (1.5 mL) was added, followed by the addition of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (95.2 mg, 0.39 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (222.2 mg, 0.585 mmol), and N,N-diisopropylethylamine (251.6 mg, 1.95 mmol). After the reaction was carried out at room temperature for 1 h, LC-MS showed the completion of the reaction. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, dichloromethane / methanol = 10 / 1) to obtain compound 10-2 (129 mg) with a yield of 59.4%. LC-MS(ESI) [M+H]+: 557.1.

[0370] Step 3: Preparation of compound 10-3

[0371] At room temperature, intermediate 10-2 (69 mg, 0.124 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of 3,6-dihydro-2H-pyran-4-boronic acid (23.8 mg, 0.186 mmol), copper(II) acetate monohydrate (49.9 mg, 0.25 mmol), and triethylamine (37.6 mg, 0.372 mmol). After the reaction was carried out at room temperature for 16 h, LC-MS showed the completion of the reaction. The reaction mixture was cooled, diluted with water (10 mL), and extracted over dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile / water = 45%, formic acid system) to obtain compound 10-3 (50 mg) with a yield of 63.1%. LC-MS(ESI) [M+H]+: 639.1.

[0372] Step 4: Preparation of compound 10-4

[0373] At room temperature, intermediate 10-3 (50 mg, 0.078 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (1 mL), followed by the addition of lithium hydroxide monohydrate (13.1 mg, 0.31 mmol). After the reaction was carried out at room temperature for 0.5 h, LC-MS showed the completion of the reaction. The pH of the mixture was adjusted to 3 with dilute hydrochloric acid (1 M) and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and lyophilized to obtain the Petition 870250086442, dated 09 / 24 / 2025, page 144 / 530 83 / 114 compound 10-4 (46 mg) with a yield of 96.6%. LC-MS(ESI) [M+H]+: 611.2.

[0374] Step 5: Preparation of compound 10-5

[0375] At room temperature, intermediate 10-4 (40 mg, 0.0655 mmol) and 3-chloro-4-aminobenzotrifluoride (38.4 mg, 0.196 mmol) were dissolved in pyridine (1 mL), followed by the dropwise addition of 4 drops of phosphorus oxychloride. The reaction was carried out at room temperature for 0.5 h until the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile / water = 68%, formic acid system) to obtain target compound 10-5 (20 mg) with a yield of 38.7%. LC-MS(ESI) [M+H]+: 788.2.

[0376] Step 6: Preparation of compound 10

[0377] At room temperature, compound 10-5 (20 mg, 0.025 mmol) was dissolved in dichloromethane (5 mL). A boron trichloride solution (0.1 mL, 1 M) in dichloromethane was added and the system was purged with nitrogen. The reaction was carried out at room temperature for 2 h, and LC-MS showed the completion of the reaction. Methanol (2 mL) was added to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure. The residue was purified by preparative HPLC to obtain compound 10 (5.02 mg) with a yield of 28.8%. LC-MS(ESI) [M+H]+: 698.2.

[0378] 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 2H), 8.61 (d, J = 5.8 Hz, 1H), 8.53 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 5.52 (d, J = 66.2 Hz, 1H), 5.31 - 5.08 (m, 2H), 4.40 - 3.94 (m, 4H), 3.85 (t, J = 5.4 Hz, 2H), 3.72 - 3.39 (m, 1H), 2.82 - 2.60 (m, 3H), 2.45 - 2.35 (m, 5H), 2.16 - 1.94 (m, 2H), 1.17 (t, J = 7.5 Hz, 3H).

[0379] Example 11: Synthesis of compound 11 Petition 870250086442, dated 09 / 24 / 2025, page 145 / 530 84 / 114

[0380] Step 1: Preparation of compound 11-1

[0381] Compound 5-8 (700 mg, 1.01 mmol) was dissolved in a mixed solvent of MeOH (3 mL), THF (9 mL), and water (3 mL), followed by the addition of LiOH (85.05 mg, 3.55 mmol). The resulting mixture was reacted at 25°C for approximately 1 h until the reaction was complete. The mixture was adjusted to pH<4 with dilute hydrochloric acid and extracted with ethyl acetate (20 mL χ2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 11-1 (650 mg) with a yield of 96.8%. LC-MS (ESI) [M+H]+: 662.4.

[0382] Step 2: Preparation of compound 11-2

[0383] Compound 11-1 (350 mg, 528.84 μmol), 2-chloro-4-trifluoromethylaniline (155.14 mg, 793.27 μmol) and pyridine (209.16 mg, 2.64 mmol, 213.01 μL) were dissolved in DCM (5 mL). Phosphorus oxychloride (121.63 mg, 793.27 μmol, 73.94 μL) was added. After the addition was complete, the resulting reaction mixture was stirred at 25°C for 1 h until the starting material was completely consumed. The solvent was removed by rotary evaporation under reduced pressure. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-2 (310 mg) with a yield of 69.8%. LC-MS(ESI) [M+H]+: 839.2.

[0384] Step 3: Synthesis of compound 11-3

[0385] Compound 11-2 (310 mg, 369.32 μmol) was dissolved in methanol HCl solution (4 M, 40.00 mmol, 10 mL) and the mixture was reacted at 25°C for 1 h until the starting material was completely consumed. The reaction mixture was slowly added to a solution Petition 870250086442, dated 09 / 24 / 2025, page 146 / 530 85 / 114 saturated with sodium bicarbonate (40 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-3 (183 mg) with a yield of 69.9%. LC-MS (ESI) [M+H]+:709.2.

[0386] Step 4: Synthesis of Compound 11-4.

[0387] Compound 11-3 (183 mg, 258.07 μmol) was dissolved in DMSO (4 mL), followed by the addition of (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)boronic acid (117.20 mg, 516.14 μmol) and PhenCuPPhBr2 (87.95 mg, 154.84 μmol). The resulting reaction mixture was reacted at 90°C under an air atmosphere for 16 h until the starting material was completely consumed. The solvent was removed by rotary evaporation under reduced pressure and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-4 (200 mg) with a yield of 87.04%. LC-MS(ESI) [M+H]+:890.4.

[0388] Step 12: Synthesis of compound 11-5

[0389] Compound 11-4 (200 mg, 146.01 μmol) was dissolved in DCM (3 mL) and TFA (1.49 g, 13.06 mmol, 1 mL) was added. The resulting mixture was reacted at 25°C for approximately 2 h until the starting material was completely consumed. The reaction mixture was slowly poured into a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 5 / 1) to obtain compound 11-5 (110 mg) with a yield of 95.34%. LC-MS (ESI) [M+H]+: 790.2.

[0390] Step 13: Synthesis of compound 11-6

[0391] Compound 11-5 (100 mg, 126.55 μmol) was dissolved in DCM (4 mL) and TEA (76.83 mg, 759.27 μmol, 105.90 μL) was added. Cyclopropylsulfonyl chloride (88.95 mg, 632.73 μmol) was added slowly dropwise at 25°C. The reaction was carried out at room temperature for about 2 h until the starting material was completely consumed. The mixture was poured into a saturated sodium bicarbonate solution (10 mL) and extracted with Petition 870250086442, dated 09 / 24 / 2025, page 147 / 530 86 / 114 ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-6 (100 mg) with a yield of 88.4%. LC-MS (ESI) [M+H]+: 894.2.

[0392] Step 14: Synthesis of compound 11

[0393] Compound 11-6 (100 mg, 111.81 μmol) was dissolved in DCM (4 mL) and a boron trichloride solution (1 M, 1 mL) in dichloromethane was added. The resulting mixture was reacted at 25°C for 1 h until the starting material was completely consumed. The solvent was removed by rotary evaporation under reduced pressure. The residue was separated by preparative HPLC to obtain compound 11 (5.05 mg) with a yield of 5.62%. LC-MS (ESI) [M+H]+: 804.2.

[0394] 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 6.41 (s, 1H), 5.16 (s, 2H), 4.49 (d, J = 12.5 Hz, 1H), 4.02 (s, 2H), 3.73 (d, J = 12.0 Hz, 2H), 3.55 (s, 2H), 3.46 (d, J = 6.5 Hz, 3H), 3.19 (s, 4H), 2.98 - 2.81 (m, 5H), 2.71 (d, J = 10.8 Hz, 2H), 2.44 (s, 3H), 1.17 (s, 3H).

[0395] Example 12: Synthesis of compound 12

[0396] Step 1: Synthesis of compound 12-1

[0397] Compound 5-11 (100 mg, 162.96 μmol), 4-pentafluorosulfanilaniline (42.86 mg, 195.55 μmol) and pyridine (64.45 mg, 814.78 μmol, 65.64 μL) were dissolved in dichloromethane (3 mL). Phosphorus oxychloride (37.48 mg, 244.43 μmol) was added. After the addition was complete, the resulting reaction system was stirred at 25°C for 1 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 12-1 (116 mg, 142.36 μmol) with a yield of 87.36%. LC-MS (ESI) [M+H]+: 815.2. Petition 870250086442, dated 09 / 24 / 2025, page 148 / 530 87 / 114

[0398] Step 2: Synthesis of compound 12

[0399] Compound 12-1 (106 mg, 130.09 μmol) was dissolved in DCM (3 mL). A boron trichloride solution (1 M, 2 mL) in dichloromethane was added. The reaction was carried out at 25°C for about 1 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 12 (4.5 mg, 6.21 μmol) with a yield of 4.77%. LCMS (ESI) [M+H]+:725.2.

[0400] Ή NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 7.88 (d, J = 9.3 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 6.41 (s, 1H), 4.99 (s, 2H), 4.49 (d, J = 11.3 Hz, 1H), 4.27 (s, 2H), 3.89 (s, 2H), 3.75 (d, J = 30.6 Hz, 2H), 3.51 (s, 1H), 3.19 (s, 2H), 2.90 (s, 3H), 2.71 (s, 3H), 2.43 (s, 3H), 1.15 (s, 3H).

[0401] Example 13: Synthesis of compound 13 OBn OBn

[0402] Step 1: Synthesis of compound 13-1

[0403] Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 3-chloro-5(trifluoromethyl)pyridin-2-amine (64 mg, 325.4 μmol) and pyridine (64.4 mg, 813.5 μmol) were dissolved in dichloromethane (5 mL). Phosphorus oxychloride (49.9 mg, 325.4 μmol) was added and the resulting mixture was stirred at 25°C for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 13-1 (40 mg) with a yield of 31%. LC-MS (ESI) [M+H]+: 793.2.

[0404] Step 2: Synthesis of compound 13

[0405] Under a nitrogen atmosphere, compound 13-1 (16 mg, 20.2 μmol) was added to trifluoroacetic acid (1 mL) and the mixture was heated to 90°C and reacted for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and then, Petition 870250086442, dated 09 / 24 / 2025, page 149 / 530 88 / 114 The resulting residue was purified by preparative HPLC to obtain compound 13 (3.0 mg) with a yield of 21%. LC-MS (ESI) [M+H]+:703.2.

[0406] 1H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 6.89 (s, 1H), 5.54 (s, 2H), 4.39 (s, 2H), 4.12 (s, 1H), 4.00 (s, 2H), 3.92 (s, 2H), 3.50 (s, 3H), 3.15 (s, 2H), 2.93 (s, 3H), 2.74 (s, 1H), 2.54 (s, 3H), 1.34 (s, 3H).

[0407] Example 14: Synthesis of compound 14

[0408] Step 1: Synthesis of compound 14-1

[0409] Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 5-chloro-2-methyl-4-(trifluoromethyl)aniline (37.1 mg, 177.2 μmol), and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL). A solution of phosphorus oxychloride (27.2 mg, 177.2 μmol) in dichloromethane (0.2 mL) was added, and the resulting mixture was stirred at 25°C for 0.5 h until the reaction was complete. The reaction mixture was poured into water and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 14-1 (110 mg) with a yield of 84%. LC-MS (ESI) [M+H]+: 806.4.

[0410] Step 2: Synthesis of compound 14

[0411] Under a nitrogen atmosphere, compound 14-1 (150 mg, 184.2 μmol) was added to trifluoroacetic acid (5 mL). The reaction was carried out at 90°C for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 14 (99.7 mg) with a yield of 76%. LC-MS(ESI) [M+H]+:716.3.

[0412] ΗI NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 10.11 (s, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 6.79 - 6.72 (m, 1H), 5.27 (s, 2H), 4.51 (d, J = 12.4 Hz, 1H), 4.33 (q, J = 2.9 Petition 870250086442, dated 09 / 24 / 2025, p. 150 / 530 89 / 114 Hz, 2H), 3.91 (t, J = 5.5 Hz, 2H), 3.70 (d, J = 11.4 Hz, 2H), 3.49 (d, J = 12.6 Hz, 1H), 3.23 (s, 1H), 3.08 - 2.91 (m, 3H), 2.78 (d, J = 23.3 Hz, 3H), 2.59 (d, J = 11.4 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H).

[0413] Example 15: Synthesis of compound 15

[0414] Step 1: Synthesis of compound 15-1

[0415] Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 2-chloro-5-fluoro-4-(trifluoromethyl)aniline (37.8 mg, 177.2 μmol) and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL). Phosphorus oxychloride (27.2 mg, 177.2 μmol) was added and the resulting mixture was stirred at 25°C for 0.5 h until the reaction was complete. The reaction mixture was poured into water and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 15-1 (120 mg) with a yield of 87%. LC-MS(ESI) [M+H]+: 810.3.

[0416] Step 2: Synthesis of compound 15

[0417] Under a nitrogen atmosphere, compound 15-1 (100 mg, 117.3 μmol) was added to trifluoroacetic acid (5 mL). The mixture was heated to 90°C and reacted for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 15 (70.2 mg) with a yield of 83%. LC-MS(ESI) [M+H]+=720.2.

[0418] 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.24 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 8.02 (d, J = 7.3 Hz, 1H), 6.74 (t, J = 1.5 Hz, 1H), 5.35 (s, 2H), 4.51 (d, J = 12.5 Hz, 1H), 4.31 (d, J = 3.0 Hz, 2H), 3.90 (t, J = 5.5 Hz, 2H), 3.77 - 3.62 (m, 2H), 3.49 (d, J = 12.6Hz, 1H), 3.22 (t, J = 12.0 Hz, 1H), 2.97 (dd, J = 11.3, 5.0 Hz, 3H), 2.77 (d, J = 22.1 Hz, Petition 870250086442, dated 09 / 24 / 2025, pp. 151 / 530 90 / 114 3H), 2.58 (d, J = 11.5 Hz, 1H), 2.44 (s, 3H), 1.18 (t, J = 7.4 Hz, 3H).

[0419] Example 16: Synthesis of compound 16

[0420] Step 1: Synthesis of compound 16-1

[0421] Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), bicyclo[4.2.0]octa-1(6), 2,4-trien-3-amine (28.7 mg, 241.1 μmol) (synthesized with reference to WO2023284837) and pyridine (63.6 mg, 803.7 μmol, 64.75 μL) were dissolved in dichloromethane (5 mL), followed by the addition of phosphorus oxychloride (29.6 mg, 192.89 μmol). The resulting mixture was stirred at 25°C for 1 h until the reaction was complete. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (3 mL) and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 16-1 (75 mg) with a yield of 61%. LC-MS (ESI) [M+H]+: 716.4.

[0422] Step 2: Synthesis of compound 16

[0423] Under a nitrogen atmosphere, compound 16-1 (75 mg, 98.2 μmol) was added to trifluoroacetic acid (1.5 mL). The mixture was heated to 90°C and reacted for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 16 (29.5 mg) with a yield of 48%. LC-MS(ESI) [M+H]+: 626.4.

[0424] 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.23 (s, 1H), 8.57 (s, 1H), 7.37 (s, 1H), 7.28 (dd, J = 8.1, 1.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 5.10 (s, 2H), 4.50 (d, J = 12.5 Hz, 1H), 4.31 (d, J = 3.0 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.74-3.65 (m, 2H), 3.48 (d, J = 12.8 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 3.08 (s, 4H), 2.97 (d, J = 8.8 Hz, 3H), 2.76 (d, J = 21.6 Hz, 3H), 2.57 (d, J = 11.5 Hz, 1H), 2.44 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H). Petition 870250086442, dated 09 / 24 / 2025, p. 152 / 530 91 / 114

[0425] Example 17: Synthesis of compound 17

[0426] Step 1: Synthesis of compound 17-1

[0427] Under a nitrogen atmosphere, compound 4-11 (120 mg, 195.2 μmol), 2,3-dihydro-1H-inden-5-amine (38.5 mg, 289.3 μmol), and pyridine (76.3 mg, 964.5 pmol) were dissolved in dichloromethane (5 mL). Phosphorus oxychloride (35.5 mg, 231.5 μmol) was added, and the resulting mixture was stirred at 25°C for 1 h until the reaction was complete. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (3 mL) to quench and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 17-1 (120 mg) with a yield of 81%. LC-MS (ESI) [M+H]+: 730.2.

[0428] Step 2: Synthesis of compound 17

[0429] Under a nitrogen atmosphere, compound 17-1 (120 mg, 155.9 μmol) was added to trifluoroacetic acid (1.0 mL). The reaction was stirred at 90°C for 1 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain compound 17 (67.6 mg) with a yield of 68%. LC-MS(ESI) [M+H]+:640.4.

[0430] 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.53 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.1, 2.0 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.75 - 6.71 (m, 1H), 5.10 (s, 2H), 4.50 (d, J = 12.8 Hz, 1H), 4.31 (q, J = 2.9 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.76 - 3.65 (m, 2H), 3.50 (d, J = 12.8 Hz, 1H), 3.22 (t, J = 12.3 Hz, 2H), 2.97 (d, J = 8.9 Hz, 3H), 2.80 (q, J = 7.0 Hz, 7H), 2.57 (d, J = 10.9 Hz, 1H), 2.43 (s, 3H), 2.02 - 1.95 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H).

[0431] Example 18: Synthesis of compound 18 Petition 870250086442, dated 09 / 24 / 2025, page 153 / 530 92 / 114

[0432] Step 1: Synthesis of compound 18-1

[0433] Compound 4-6 (9 g, 15.4 mmol) was added to ethanol (400 mL), followed by the addition of palladium on carbon (5%, 1.6 g) and palladium hydroxide on carbon (5%, 2.2 g). The reaction was heated under reflux in a hydrogen atmosphere for 16 h until the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The resulting crude product was purified by suspension with a mixed solvent (petroleum ether: ethyl acetate = 5:1) to obtain compound 18-1 (6 g) with a yield of 85%. LC-MS (ESI) [M+H]+: 435.4.

[0434] Step 2: Synthesis of Compound 18-2.

[0435] Compound 18-1 (6.75 g, 14.43 mmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (3.69 g, 28.86 mmol) and pyridine (11.41 g, 144.28 mmol, 11.62 mL) were dissolved in dichloromethane (140 mL). After ultrasound to obtain a clear solution, copper(II) acetate (7.86 g, 43.28 mmol) was added. The reaction was carried out at room temperature under an oxygen atmosphere for 2 h until the reaction was complete. The reaction mixture was filtered through diatomaceous earth and the filtrate was sequentially washed with water (3 x 30 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under pressure. Petition 870250086442, dated 09 / 24 / 2025, page 154 / 530 93 / 114 reduced. The resulting crude product was purified by silica gel column (dichloromethane:methanol = 20:1) to obtain compound 18-2 (7.43 g) with a yield of 92%. LC-MS (ESI) [M+H]+: 517.3.

[0436] Step 3: Synthesis of compound 18-3

[0437] Under a nitrogen atmosphere, compound 18-2 (7.43 g, 13.31 mmol) was dissolved in a dioxane hydrochloride solution (4 mol / L, 75 mL). The reaction was stirred at 25°C for 0.5 h until the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water (100 mL) was added and the pH was adjusted to 8 with a saturated sodium carbonate solution. The mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain compound 18-3 (5.4 g) with a yield of 93%. LC-MS (ESI) [M+H]+: 417.4.

[0438] Step 4: Synthesis of Compound 18-4.

[0439] Under a nitrogen atmosphere, compound 18-3 (1.72 g, 4.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). 5-Methoxypyrimidine-4-carboxylic acid (0.76 g, 4.96 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.14 g, 8.26 mmol) and N,N-diisopropylethylamine (0.53 g, 4.13 mmol) were added. The reaction was stirred at 25°C for 16 h until the reaction was complete. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain compound 18-4 (2.0 g) with a yield of 88%. LC-MS (ESI) [M+H]+: 553.4.

[0440] Step 5: Synthesis of compound 18-5

[0441] Under a nitrogen atmosphere, compound 18-4 (2.5 g, 4.5 mmol) was dissolved in tetrahydrofuran / water (16 mL / 4 mL) and lithium hydroxide monohydrate (0.76 g, 18.1 mmol) was added. The reaction system was stirred at 25°C for 1 h until the reaction was complete. Diluted hydrochloric acid (2 mol / L) was added dropwise to adjust the pH to 2. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The Petition 870250086442, dated 09 / 24 / 2025, page 155 / 530 94 / 114 organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain compound 18-5 (2.0 g) with a yield of 84%. LC-MS (ESI) [M+H]+: 525.2.

[0442] Step 6: Synthesis of Compound 18-6.

[0443] Under a nitrogen atmosphere, compound 18-5 (0.2 g, 0.38 mmol) was dissolved in dichloromethane (10 mL) and 2-chloro-4-trifluoromethylaniline (0.089 g, 0.42 mmol) and pyridine (0.30 g, 3.8 mmol) were added. A solution of phosphorus oxychloride (0.07 g, 0.46 mmol) in dichloromethane (3 mL) was then added. The reaction was carried out at 25°C for 15 min until the reaction was complete. The reaction mixture was cooled, diluted with water (10 mL) and extracted over dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to obtain compound 18-6 (0.1 g) with a yield of 37%. LC-MS (ESI) [M+H]+: 702.2.

[0444] Step 7: Synthesis of compound 18

[0445] Under a nitrogen atmosphere, compound 18-6 (0.15 g, 0.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and aluminum trichloride (0.28 g, 2.1 mmol) was added. The reaction was carried out in a microwave reactor at 150°C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to obtain compound 18 (20 mg) with a yield of 14%. LC-MS (ESI) [M+H]+: 688.4.

[0446] 1H NMR (400 MHz, MeOD-d4) δ 8.65 (s, 1H), 8.41 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.6, 1.5 Hz, 1H), 6.88 (s, 1H), 5.44 - 5.36 (m, 2H), 4.69 (d, J = 12.6 Hz, 1H), 4.39 (d, J = 2.8 Hz, 2H) (d, J = 11.3 Hz, 1H), 1.33 (t, J = 5.0 Hz, 3H).

[0447] Example 19: Synthesis of compound 19 Petition 870250086442, dated 09 / 24 / 2025, p. 156 / 530 95 / 114

[0448] Step 1: Synthesis of compound 19-1

[0449] Under a nitrogen atmosphere, compound 18-3 (0.26 g, 0.62 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 3-(benzyloxy)picolinic acid (0.17 g, 0.74 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g, 0.74 mmol) and N,N-diisopropylethylamine (0.4 g, 3.1 mmol). The reaction was stirred at 25°C for 1 h until the reaction was complete. The reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol / dichloromethane = 6%) to obtain compound 19-1 (0.35 g) with a yield of 89%. LC-MS (ESI) [M+H]+: 628.3.

[0450] Step 2: Synthesis of Compound 19-2.

[0451] Under a nitrogen atmosphere, compound 19-1 (0.28 g, 0.45 mmol) was dissolved in tetrahydrofuran / water (5 mL / 1 mL) and lithium hydroxide monohydrate (57 mg, 1.35 mmol) was added. The reaction was stirred at 25°C for 1 h until the reaction was complete. The reaction mixture was adjusted to pH = 2 with dilute hydrochloric acid (2 mol / L), diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, Petition 870250086442, dated 09 / 24 / 2025, page 157 / 530 96 / 114 washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 19-2 (0.24 g) with a yield of 90%. LCMS (ESI) [M+H]+: 600.3.

[0452] Step 3: Synthesis of compound 19-3

[0453] Under a nitrogen atmosphere, compound 19-2 (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of the intermediate 2-chloro-5-fluoro-4(trifluoromethyl)aniline (44 mg, 0.20 mmol) and pyridine (130 mg, 1.70 mmol). A solution of phosphorus oxychloride (31 mg, 0.20 mmol) in dichloromethane (3 mL) was then added. The reaction was stirred at room temperature for 15 min until the reaction was complete. The reaction mixture was cooled, diluted with water (6 mL), and extracted over dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to obtain compound 19-3 (66 mg) with a yield of 50%. LC-MS (ESI) [M+H]+: 795.3.

[0454] Step 4: Synthesis of compound 19

[0455] Under a nitrogen atmosphere, compound 19-3 (56 mg, 0.70 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 90°C and stirred for 3 h until the reaction was complete. The reaction mixture was concentrated by drying under reduced pressure. The residue was diluted with water (6 mL) and extracted with dichloromethane (5 mL x 3). The organic phases were combined, washed sequentially with water (5 mL x 6) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to obtain compound 19 (7.0 mg) with a yield of 14%. LC-MS (ESI) [M+H]+: 705.3.

[0456] 1H NMR (400 MHz, MeOD-d4) δ 8.17 (d, J = 12.6 Hz, 1H), 8.09 (s, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 2.8 Hz, 2H), 6.87 (s, 1H), 5.43 (s, 2H), 4.77 - 4.66 (m, 1H), 4.42 4.33 (m, 2H), 3.99 (t, J = 5.4 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.76 - 3.60 (m, 1H), 3.38 (d, J = 22.3 Hz, 1H), 3.18 - 3.09 (m, 3H), 2.96 - 2.84 (m, 3H), 2.79 - 2.68 (m, 1H), 1.32 (t, J = 7.4Hz, 3H).

[0457] Example 20: Synthesis of compound 20 Petition 870250086442, dated 09 / 24 / 2025, p. 158 / 530 97 / 114

[0458] Step 1: Synthesis of compound 20-1

[0459] Under a nitrogen atmosphere, compound 19-2 (100 mg, 0.17 mmol), 2-chloro-4-trifluoromethylaniline (48.92 mg, 0.25 mmol), and phosphorus oxychloride (76.71 mg, 500.3 μmol) were dissolved in DCM (6 mL), followed by the addition of pyridine (79.15 mg, 1.0 mmol). The resulting mixture was stirred and reacted at 25°C for 0.5 h until the reaction was complete. The reaction mixture was cooled, diluted with water (6 mL), and extracted over dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 10 / 1) to obtain compound 20-1 (122 mg) with a yield of 94%. LC-MS (ESI) [M+H]+: 777.2.

[0460] Step 2: Synthesis of compound 20

[0461] Under a nitrogen atmosphere, compound 20-1 (122 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (1 mL), heated to 90°C and stirred for 0.5 h until the reaction was complete. The reaction mixture was concentrated by drying under reduced pressure. The residue was purified by HPLC to obtain compound 20 (7.2 mg) with a yield of 6.7%. LC-MS (ESI) [M+H]+: 687.2.

[0462] 1H NMR (400 MHz, MeOD-d4) δ 8.15 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.60 (d, J= 10.1 Hz, 1H), 7.34 (s, 2H), 6.86 (s, 1H), 5.38 (s, 2H), 4.36 (s, 2H), 3.94 (d, J = 36.8 Hz, 4H), 3.64 (s, 1H), 3.45 (s, 2H), 3.15 (s, 3H), 2.90 (s, 3H), 2.69 (s, 1H), 1.33 (s, 3H).

[0463] Example 21: Synthesis of compound 21 Petition 870250086442, dated 09 / 24 / 2025, page 159 / 530 98 / 114 4-11

[0464] Step 1: Synthesis of compound 21-1

[0465] Under a nitrogen atmosphere, compounds 4-11 (33.6 mg, 54.7 μmol), 4-(pentafluorothio)aniline (11.98 mg, 54.7 μmol), and pyridine (21.6 mg, 273.3 μmol) were dissolved in dichloromethane (5 mL). A solution of phosphorus oxychloride (25.2 mg, 164.0 μmol) in dichloromethane (0.5 mL) was added. The resulting mixture was stirred and reacted at 25°C for 1 h until the reaction was complete. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (3 mL) to quench and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The resulting crude product was separated by silica gel column chromatography (dichloromethane:methanol = 9:1) to obtain compound 21-1 (42 mg) with a yield of 94%. LC-MS (ESI) [M+H]+: 816.2.

[0466] Step 2: Synthesis of compound 21

[0467] Under a nitrogen atmosphere, compound 21-1 (42 mg, 51.5 μmol) was dissolved in a dichloromethane solution (5 mL), followed by the addition of boron trichloride (25.13 mg, 214.51 μmol, 0.2 mL). The reaction was stirred at 25°C for 1 h until the reaction was complete. Methanol (1 mL) was added to quench the reaction. After concentration under reduced pressure, the resulting crude product was purified by preparative HPLC to obtain compound 21 (12 mg) with a yield of 39%. LC-MS(ESI) [M+H]+=726.2.

[0468] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.10 (s, 1H), 8.56 (s, 1H), 7.88 (d, J = 9.3 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 6.70 - 6.52 (m, 1H), 5.36 (s, 2H), 4.50 (d, J = 12.4 Hz, 1H), 4.33 (q, J = 2.8 Hz, 2H), 3.93 (t, J = 5.4 Hz, 2H), 3.70 (t, J = 12.0 Hz, 2H), 3.47 (d, J = 12.7 Hz, 1H), 3.20 (d, J = 11.1 Hz, 2H), 3.09 - 2.91 (m, 3H), 2.76 (d, J = 24.2 Hz, 3H), 2.57 (d, J = 11.4 Hz, 1H), 2.44 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H).

[0469] Example 22: Synthesis of compound 22 Petition 870250086442, dated 09 / 24 / 2025, page 160 / 530 99 / 114

[0470] Step 1: Synthesis of compound 22-1

[0471] Under a nitrogen atmosphere, compound 4-11 (120 mg, 195.2 μmol), 2,4-dichloro 5-Fluoroaniline (52.7 mg, 292.9 μmol) and pyridine (77.2 mg, 976.2 μmol) were dissolved in dichloromethane (3 mL), followed by the addition of phosphorus oxychloride (44.9 mg, 292.9 μmol). The resulting mixture was stirred and reacted at 25°C for 1 h until the reaction was complete. The reaction mixture was quenched with water (3 mL) and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The resulting crude product was separated by silica gel column chromatography (dichloromethane:methanol = 19:1) to obtain compound 22-1 (117 mg) with a yield of 87%. LC-MS (ESI) [M+H]+: 776.4.

[0472] Step 2: Synthesis of compound 22

[0473] Under a nitrogen atmosphere, compound 22-1 (117 mg, 150.7 μmol) was dissolved in trifluoroacetic acid (2.5 mL). The reaction was stirred at 90°C for 0.5 h until the reaction was complete. After concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (20 mL), washed with water (5 mL), and extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by suspension with petroleum ether / ethyl acetate (4:1) to obtain compound 22 (51.7 mg) with a yield of 50%. LC-MS(ESI) [M+H]+: 686.2.

[0474] Ή NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.58 (s, 1H), 8.00-7.90 (m, 2H), 6.826.70 (m, 1H), 5.28 (s, 2H), 4.51 (d, J = 12.0 Hz, 1H), 4.39-4.29 (m, 2H), 3.95-3.86 (m, 2H), 3.80-3.64 (m, 2H), 3.54-3.45 (m, 1H), 3.28-3.16 (m, 1H), 3.09-2.88 (m, 3H), 2.86-2.73 (m, 3H), 2.66-2.55(m,1H), 2.44 (s, 3H), 1.19 (t, J = 8.0 Hz, 3H).

[0475] Example 23: Synthesis of compound 23 Petition 870250086442, dated 09 / 24 / 2025, page 161 / 530 100 / 114

[0476] Step 1: Synthesis of compound 23-1

[0477] Under a nitrogen atmosphere, the compound 4-11 (100 mg, 161.1 μmol), 4-amino 2,5-Difluorobenzotrifluoride (34.9 mg, 177.2 μmol) and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL), followed by the addition of a solution of phosphorus oxychloride (27.2 mg, 177.2 μmol) in dichloromethane (0.2 mL). The resulting mixture was stirred and reacted at 25°C for 0.5 h until the reaction was complete. The reaction mixture was quenched with water (3 mL) and extracted with dichloromethane (2 x 5 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 23-1 (120 mg) with a yield of 89%. LC-MS (ESI) [M+H]+: 794.4.

[0478] Step 2: Synthesis of compound 23

[0479] Under a nitrogen atmosphere, compound 23-1 (110 mg, 119.7 μmol) was dissolved in trifluoroacetic acid (5 mL). The reaction was stirred at 90°C for 0.5 h until the reaction was complete. After concentration under reduced pressure, water (10 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 90:10) to obtain compound 23 (63.8 mg) with a yield of 75%. LC-MS(ESI) [M+H]+: 704.3.

[0480] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.23 (s, 1H), 8.57 (s, 1H), 8.20 (dd, J = 12.6, 6.1 Hz, 1H), 7.88 (dd, J = 10.6, 6.6 Hz, 1H), 6.73 (p, J = 1.7 Hz, 1H), 5.30 (s, 2H), 4.51 (d, J = 12.4 Hz, 1H), 4.31 (q, J = 2.9 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.76 - 3.64 (m, 2H), 3.49 (d, J = 12.6 Hz, 1H), 3.22 (t, J = 11.8 Hz, 1H), 2.97 (d, J = 9.6 Hz, 3H), 2.76 (d, J = 19.9 Hz, 3H), 2.58 (d, J = 11.2 Hz, 1H), 2.44 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H).

[0481] Comparative Example Petition 870250086442, dated 09 / 24 / 2025, p. 162 / 530 101 / 114

[0482] Example 42 of WO2022249060A1 was used as the reference compound. HRO761 and the compound were prepared according to the method described in this patent.

[0483] Experimental Example 1: WRN Helicase Activity Assay

[0484] 1. Experimental instruments

[0485] Information regarding the instruments used in this experimental example is presented in Table 1.

[0486] Table 1 Instrument Name: Eppendorf 5810R Centrifuge; Instrument Manufacturer: PerkinElmer EnVision-2015 Microplate Reader; Model: Eppendorf 5810R

[0487] 2. Experimental materials

[0488] The WRN enzyme used in the experiment has a His-TEV marker at the N-terminus and is expressed in eukaryotic cells with a purity of 90%. The two single-stranded DNAs used for the assay are labeled with BHQ2 and Cy5, respectively. When two fluorophores are close together (when the DNA is in a double-stranded state), no fluorescence signal is detected due to the quenching effect. WRN has helicase activity, which allows the unwinding of double-stranded DNA to form single strands, thus generating a fluorescence signal. Information on other reagents and consumables needed for the experiment is shown in Table 2.

[0489] Table 2 Reagent Brand Cat. No. Bicine Sigma B8660 KCl Sigma P9541 MgCl2 Sigma M1028 F-127 Sigma P2443 TCEP Sigma 646547 BSG Sigma G9391 Petition 870250086442, dated 09 / 24 / 2025, page 163 / 530 102 / 114 Tris BBI Life Sciences A600194-0500 DTT Sigma V900830-5G NaCl BBI Life Sciences A610476-001 DNA GenScript NA ATP Sigma A7699 96-well V-bottom plate Beyotime FPT019 384-well plate Greiner 781209

[0490] 3. Experimental methods

[0491] Two labeled single-stranded DNA strands were annealed to form double-stranded DNA. Annealing buffer: 12 mM Tris (pH 8.0), 300 mM NaCl, 12 mM MgCh, 2 mM DTT. Annealing program: 95°C, 5 min.

[0492] 2* WRN enzyme (2 nM) and 2* substrate (100 nM double-stranded DNA, 1000 nM capture DNA, 100 μM ATP) were prepared using buffer (20 mM Bicin, 10 mM KCl, 1 mM MgCh, 0.005% BSG, 1 mM TCEP, 0.1% F-127, pH 7.5). The test compound was dissolved in 10 mM DMSO and gradient diluted using a 96-well V-bottom plate. 0.5 μL of compound was added to 25 pL of 2* WRN enzyme and incubated at room temperature for 30 min. 25 pL of 2* substrate were added and the reaction was carried out at room temperature for 30 min. The detection was performed using a microplate reader with an excitation wavelength of 620 nm and an emission wavelength of 685 nm.

[0493] 4 Data Analysis

[0494] The concentration-effect curve was fitted using GraphPad Prism 8 software and the compound concentration for 50% inhibition (IC50) was calculated. The percentage inhibition for each compound concentration was first calculated and then the concentration-effect curve was fitted using the log(inhibitor) vs. normalized response - Variable slope equation in GraphPad Prism 8 software to obtain the IC50.

[0495] Inhibition rate (%) = (average fluorescence intensity of positive control wells - fluorescence intensity of composite wells) / (average intensity of Petition 870250086442, dated 09 / 24 / 2025, page 164 / 530 103 / 114 fluorescence of positive control wells - average fluorescence intensity of negative control wells) x 100

[0496] Positive control: 25 μL 2x WRN enzyme + 0.5 μL DMSO + 25 μL 2x substrate

[0497] Negative control: 25 μL 2x buffer + 0.5 μL DMSO + 25 μL 2x substrate

[0498] The results are shown in Table 3.

[0499] Table 3 Example WRN helicase activity (IC50 nM) Example 4 60.92 Example 15 70.15 Example 22 72.12

[0500] The above assay indicates that the compounds in this disclosure exhibit favorable WRN helicase activity and have the potential to be further developed as WRN helicase inhibitors.

[0501] Experimental Example 2 WRN Hydrolase Activity Assay

[0502] 1. Experimental instruments

[0503] Information regarding the instruments used in this experimental example is presented in Table 4.

[0504] Table 4 Instrument Name: Eppendorf 5810R Centrifuge; Instrument Manufacturer: PerkinElmer EnVision-2015 Microplate Reader; Model: Eppendorf 5810R

[0505] 2. Experimental materials

[0506] The WRN enzyme used in the experiment has a His-TEV marker at the N-terminus and is expressed in eukaryotic cells with a purity of 90%. The assay kit (ADP-Glo™ Kinase Assay) was purchased from Promega (Cat. No. V9101), aliquoted, and then stored in the refrigerator at -40°C. This kit could quantitatively detect the amount of ADP generated in the reaction. ATP hydrolyzed by WRN to produce ADP. The ADP-Glo ​​reagent was added to deplete excess ATP in the reaction system, followed by the addition of Petition 870250086442, dated 09 / 24 / 2025, page 165 / 530 104 / 114 Kinase detection reagent is used to convert the ADP produced by the reaction into ATP and produce chemiluminescence. The enzymatic activity of WRN can be reflected by detecting the chemiluminescence signal using a microplate reader. Information on other reagents and consumables needed for the experiment is shown in Table 5.

[0507] Table 5 Reagent Brand Cat. No. Bicine Sigma B8660 KCl Sigma P9541 MgCl2 Sigma M1028 Tween 20 Thermo Fisher 28320 Tris BBI Life Sciences A600194-0500 NaCl BBI Life Sciences A610476-001 TCEP Sigma 646547 BSG Sigma G9391 DNA GenScript NA ATP Sigma A7699 96-well V-bottom plate Beyotime FPT019 384-well plate PE 6008280

[0508] 3. Experimental methods

[0509] Single-stranded DNA was annealed to form double-stranded DNA. Annealing buffer 5*: 50 mM Tris pH 8.0, 100 mM NaCl. Annealing program: 95°C, 5 min.

[0510] 2* WRN enzyme (1 nM) and 2* substrate (1 nM double-stranded DNA, 100 μM ATP) were prepared using a buffer (20 mM Bicin (pH 7.5), 10 mM KCl, 10 mM MgCl2, 0.005% BSG, 0.002% Tween 20, 1 mM TCEP). The test compound was dissolved in 10 mM DMSO and gradient diluted using a 96-well V-bottom plate. First, 25 pL of 2* WRN enzyme and 0.5 pL of compound were added to a 96-well plate and incubated at room temperature for 30 min. Then, 25 pL of Petition 870250086442, dated 09 / 24 / 2025, page 166 / 530 105 / 114 substrate 2* were added and the reaction was carried out at room temperature for 60 min. 5 μL were removed from the reaction plate and transferred to a 384-well plate for detection. 5 μL of ADP-Glo ​​reagent were added and incubated at room temperature for 60 min, followed by the addition of 10 μL of Kinase Detection Reagent and incubation at room temperature for 40 min. The chemiluminescence signal was detected using a microplate reader.

[0511] 4 Data Analysis

[0512] The concentration-effect curve was fitted using GraphPad Prism 8 software and the compound concentration for 50% inhibition (IC50) was calculated. The percentage inhibition for each compound concentration was first calculated and then the concentration-effect curve was fitted using the log(inhibitor) vs. normalized response - Variable slope equation in GraphPad Prism 8 software to obtain the IC50.

[0513] Inhibition rate (%) = (average luminescence intensity of positive control wells - luminescence intensity of composite wells) / (average luminescence intensity of positive control wells - average luminescence intensity of negative control wells) * 100

[0514] Positive control: 25 pL 2* WRN enzyme + 0.5 pL DMSO + 25 pL 2* substrate

[0515] Negative control: 25 pL 2* buffer + 0.5 pL DMSO + 25 pL 2* substrate

[0516] The results are shown in Table 6.

[0517] Table 6 Example WRN helicase activity (IC50 nM) Example 4 88.53 Example 5 79.07 Example 6 134.5 Example 7 86.94 Example 8 118 Example 9 94.9 Example 10 237.8 Petition 870250086442, dated 09 / 24 / 2025, page 167 / 530 106 / 114 Example 11 65.27 Example 12 85.98 Example 13 104 Example 14 30.8 Example 15 34.29 Example 16 42.59 Example 17 34.66 Example 18 64.26 Example 19 44.29 Example 20 35.5 Example 21 24.39 Example 22 46.77 Example 23 41.94

[0518] The above test results indicate that the compounds in this disclosure exhibit excellent WRN hydrolase activity.

[0519] Experimental Example 3 Cell Proliferation Assay

[0520] 1. Experimental instruments

[0521] Information regarding the instruments used in this experimental example is presented in Table 7.

[0522] Table 7 Instrument Name Instrument Manufacturer Model Biological Safety Cabinet Thermo 1300 SERIES A2 CO2 Incubator Thermo 371 Beckman CoμLter Vi-CELL XR Cell Counter Eppendorf 5810R Centrifuge Microplate Reader Molecular Devices SpectraMax i3x

[0523] 2. Experimental materials

[0524] Information about other reagents and consumables needed for the experiment Petition 870250086442, dated 09 / 24 / 2025, page 168 / 530 107 / 114 are shown in Table 8.

[0525] Table 8 Reagent Brand Cat. No. Assay Kit Celltiter Glo Promega G7572 Leibovitz's L-15 MediuM Gibco 11415-064 F12K MediuM Gibco 21127-022 McCoy5A MediuM Gibco 16600-082 DMSO Sangon Biotech A503039-0250 PBS Gibco 10010-023 FBS Gibco 10091-148 0.25% Trypsin-EDTA Gibco 25200-056 PenStrep Gibco 15140-122 96-well plate Beyotime FCP965

[0526] 3. Experimental methods

[0527] SW48 cells were plated at a density of 1,500 cells / well and LoVo, HCT116, and SW620 cells were plated at a density of 800 cells / well in a 96-well cell culture plate and cultured in an incubator at 37°C overnight. Test compounds, which were gradient-diluted with DMSO, were added, and after incubation for 5 days, cell viability was detected using a CellTiter-Glo kit. The CellTiter-Glo reagent was equilibrated at room temperature, and an appropriate amount was added to the cell plate, followed by shaking at room temperature for 12 min. The luminescence signal was detected using a microplate reader.

[0528] 4 Data Analysis

[0529] The luminescence signal values ​​of the DMSO-treated wells and cell-free wells were used as negative and positive controls, respectively, to calculate the compound's inhibition rate on cell proliferation. The concentration-inhibition curve was fitted using the log(inhibitor) vs. normalized response -- Variable slope equation in GraphPad Prism 8 software to obtain the IC50.

[0530] Inhibition rate (%) = [1 - (luminescence intensity of compound wells Petition 870250086442, dated 09 / 24 / 2025, page 169 / 530 108 / 114 average luminescence intensity of positive control wells) / (average luminescence intensity of negative control wells - average luminescence intensity of positive control wells)] x 100

[0531] The results are shown in Table 9.

[0532] Table 9 Example Cell proliferation HCT-116 (IC50 nM) SW-48 (IC50 nM) LoVo (IC50 nM) SW-620 (IC50 nM) Example 4 48.01 37.21 105.2 >25000 Example 5 1585 942.7 2709 >25000 Example 6 ND 324.5 ND >25000 Example 7 289.4 211.5 735.5 >25000 Example 8 ND 133 ND >25000 Example 10 552 330.9 871.1 >25000 Example 12 ND 316.6 ND >25000 Example 13 434.7 ND ND >25000 Example 14 ND 42.44 ND >25000 Example 15 ND 35.36 ND >25000 Example 16 ND 148.5 ND >25000 Example 17 ND 126.1 ND >25000 Example 18 ND 51.1 ND >25000 Example 19 ND 60.91 ND 20700 Example 20 ND 33.82 ND 23679 Example 22 ND 70.72 ND >25000 Example 23 ND 102.5 ND >25000 HRO761 142.9 144.2 220.5 >25000

[0533] ND indicates not detected.

[0534] The above test results indicate that the compounds in this disclosure have an inhibitory effect on the proliferation of MSI-H colorectal cancer cell lines. Petition 870250086442, dated 09 / 24 / 2025, page 170 / 530 109 / 114 SW48 and HCT116, but no inhibitory effect on MSS SW620 cells.

[0535] Experimental Example 4 Induction Assay of γH2AH

[0536] 1. Experimental instruments

[0537] Information regarding the instruments used in this experimental example is shown in Table 10.

[0538] Table 10 Instrument Name Instrument Manufacturer Model Biological Safety Cabinet Thermo 1300 SERIES A2 CO2 Incubator Thermo 371 Beckman CoμLter Vi-CELL XR Cell Counter Eppendorf 5810R Centrifuge Thermo 13687716 Shaker PerkinElmer EnVision-2015 Microplate Reader

[0539] 2. Experimental materials

[0540] Information on other reagents and consumables needed for the experiment is shown in Table 11.

[0541] Table 11 Reagent Brand Cat. No. Assay Kit Celltiter Glo Promega G7572 HTRF Detection Kits Fosfo-H2AX (SER139) PerkinElmer 64H2XPEH Leibovitz's L-15 MediuM Gibco 11415-064 McCoy5A MediuM Gibco 16600-082 DMSO Sangon Biotech A503039-0250 PBS Gibco 10010-023 FBS Gibco 10091-148 0.25% Trypsin-EDTA Gibco 25200-056 Petition 870250086442, dated 09 / 24 / 2025, p. 171 / 530 110 / 114 PenStrep Gibco 15140-122 96-well plate Beyotime FCP965 384-well plate PerkinElmer 6007299

[0542] 3. Experimental methods:

[0543] SW48, HCT116, and SW620 cells were plated in 96-well cell culture plates at a density of 15,000–25,000 cells / well and cultured overnight in an incubator at 37°C. Test compounds, which were gradient-diluted with DMSO, were added and incubated for 2–3 days. The γ-H2AX level was detected using HTRF Fosfo-H2AX Detection Kits (SER139). Lysis buffer 4* and detection buffer were equilibrated at room temperature for later use. Lysis buffer 4* was diluted to lysis buffer 1* using ddH2O. After the medium was aspirated, 50 μL of lysis buffer 1* were added to each well and stirred at room temperature for 30 minutes for lysis.16 μL of lysate were transferred to a 384-well plate, followed by the addition of 4 μL of diluted antibody mixture (Fosfo-H2AX d2 antibody and Fosfo-H2AX I Cryptate antibody were each diluted 20 times using detection buffer, and the two antibodies were then uniformly mixed at a 1:1 volume ratio). The mixture was incubated at room temperature for 2–24 hours, and fluorescence signals at 655 nm and 615 nm were detected using a microplate reader. Parallel treatment plates were set up simultaneously in the experiment, and cell viability was detected using the CellTiter-Glo kit. The CellTiter-Glo reagent was equilibrated at room temperature, and an appropriate amount was added to the cell plate, followed by shaking at room temperature for 12 min. The luminescence signal was detected using a microplate reader.

[0544] The fluorescence signal values ​​of DMSO-treated wells and positive drug-treated wells were used as negative and positive controls, respectively, to calculate the γ-H2AΧ level induced by the compounds. The concentration-induction rate curve was fitted using the log(agonist) vs. response - Variable slope (four parameters) equation in GraphPad Prism 8 software to obtain the EC50.

[0545] Cell viability (%) = luminescence intensity of the wells Petition 870250086442, dated 09 / 24 / 2025, page 172 / 530 111 / 114 compounds / average luminescence intensity of negative control wells x 100

[0546] HTRF ratio = fluorescence signal value at 665 nm / fluorescence signal value at 615 nm X104

[0547] The results are shown in Table 12.

[0548] Table 12 Example of γ-H2AX induction: HCT-116 (EC50 nM) SW-48 (EC50 nM) SW-620 (EC50 nM) Example 4: 127.6 53.78 >10000 Example 15: 97.1 62.88 >10000 Example 22: 168.2 127.8 >10000 HRO761: 640.5 324.1 >10000

[0549] The above test results indicate that treatment with the compounds in this disclosure can significantly induce the accumulation of DNA damage (increased levels of γ-H2AΧ) in MSI-H SW48 and HCT116 colorectal cancer cell lines, but has no induction effect on MSS SW620 cells.

[0550] Experimental Example 5 Pharmacokinetic Test in Mice

[0551] 1. Experimental objective

[0552] CD-1 mice were used as test animals. Example 4, Example 22, and Comparative Example HRO761 were administered by gavage. Drug concentrations in mouse plasma at different time points were determined by LC-MS / MS to investigate the pharmacokinetic characteristics of the compounds in this disclosure in mice.

[0553] 2. Experimental scheme

[0554] 2.1 Medicinal products and experimental animals

[0555] Experimental drugs: Example 4, Example 22 and Comparative Example HRO761;

[0556] Animals: CD-1 mice, males, 24-25 g, acquired from Shanghai Jihui Laboratory Animal Care Co.,Ltd.

[0557] 2.2 Preparation of the medicine

[0558] An appropriate amount of Example 4, Example 22 and Comparative Example Petition 870250086442, dated 09 / 24 / 2025, page 173 / 530 112 / 114 HRO761 was weighed and sequentially added to an appropriate amount of dimethyl sulfoxide, solutol, and saline solution (final solvent: 5% DMSO + 10% solutol + 85% saline solution). The mixture was vortexed and sonicated to prepare a 1.0 mg / mL dosage solution.

[0559] 2.3 Administration

[0560] Three mice in gavage groups from Example 4, Example 22 and Comparative Example HRO761 were administered by oral gavage after overnight fasting (dose: 10 mg / kg, administration volume: 10 mL / kg) and the mice were fed 4 h after administration.

[0561] 3. Experimental operation

[0562] 0.04 mL of blood was collected from the animals before administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration and anticoagulated with sodium heparin. Blood samples were placed on ice after collection and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 5 min). The collected plasma was stored at -80°C before analysis.

[0563] LC-MS / MS was used to determine the content of the test compound in mouse plasma after intragastric administration.

[0564] 4. Results of pharmacokinetic parameters

[0565] Based on the calculated plasma concentrations of the compounds at different time points, the pharmacokinetic parameters of Example 4, Example 22, and Comparative Example HRO761 in mice were calculated using the winnonlin software. The pharmacokinetic parameters of Example 4, Example 22, and Comparative Example HRO761 from this disclosure are shown in Table 13.

[0566] Table 13 Compound No. Cmax, ng / mL AUC0-1, ng.h / mL Example 4 24773 51542 Example 22 24612 83414 Comparative example 11206 28343 Petition 870250086442, dated 09 / 24 / 2025, page 174 / 530 113 / 114 HRO761

[0567] The above test results indicate that the compounds in this disclosure exhibit favorable pharmacokinetic characteristics in mice.

[0568] Experimental Example 6 Pharmacokinetic Test in Rats

[0569] 1. Experimental objective

[0570] SD rats were used as test animals. Example 4, Example 15, and Comparative Example HRO761 were administered by gavage. Drug concentrations in rat plasma at different time points were determined by LC-MS / MS to investigate the pharmacokinetic characteristics of Example 4, Example 15, and Comparative Example HRO761 in rats.

[0571] 2. Experimental scheme

[0572] 2.1 Medicinal products and experimental animals

[0573] Experimental drugs: Example 4, Example 15 and Comparative Example HRO761;

[0574] Animals: SD rats, male, 240-260 g, purchased from Shanghai Jihui Laboratory Animal Care Co.,Ltd.

[0575] 2.2 Preparation of the medicine

[0576] An appropriate amount of Example 4, Example 15 and Comparative Example HRO761 was weighed and added to an appropriate amount of dimethyl sulfoxide, solutol and saline solution (final solvent: 5% DMSO + 10% solutol + 85% saline solution). The mixture was vortexed and sonicated to prepare a 1.0 mg / mL dosage solution.

[0577] 2.3 Administration

[0578] Rats in gavage groups (3 rats per group) from Example 4, Example 15 and Comparative Example HRO761 were administered by oral gavage after overnight fasting (dose: 10 mg / kg, administration volume: 10 mL / kg) and the rats were fed 4 h after administration.

[0579] 3. Experimental operation

[0580] 0.2 mL of blood was collected from the animals before administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration and anticoagulated with sodium heparin. The blood samples were placed on ice after collection and the plasma was separated by Petition 870250086442, dated 09 / 24 / 2025, page 175 / 530 114 / 114 centrifugation (centrifugation conditions: 8000 rpm, 5 min). The collected plasma was stored at -80°C before analysis.

[0581] The contents of Example 4, Example 15 and Comparative Example HRO761 in rat plasma after oral administration were determined by LC-MS / MS.

[0582] 4. Results of pharmacokinetic parameters

[0583] Based on the calculated plasma concentrations of the compounds at different time points, the pharmacokinetic parameters of Example 4, Example 15, and Comparative Example HRO761 in rats were calculated using the winnonlin software. The pharmacokinetic parameters of Example 4, Example 15, and Comparative Example HRO761 of this disclosure are shown in Table 14.

[0584] Table 14 Compound No. Cmax, ng / mL AUC0-i, ng.h / mL Example 4 19180 170483 Example 15 9016 46423 Comparative example HRO761 6965 63602

[0585] The above test results indicate that the compounds in this disclosure exhibit favorable pharmacokinetic characteristics in rats.

[0586] The illustrative embodiments of this disclosure have been described above. It should be understood that the scope of protection of this disclosure is not limited to the illustrative embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of this disclosure shall be included in the scope of protection of this disclosure. Petition 870250086442, dated 09 / 24 / 2025, page 176 / 530

Claims

1 / 24 CLAIMS 1. Compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that ring A is selected from the group consisting of 5 to 10 membered phenyl and heteroaryl, wherein the 5 to 10 membered phenyl and heteroaryl are optionally substituted by 1, 2 or 3 Ra; ring B is selected from the group consisting of 3 to 20 membered C3-20 cycloalkyl, 4 to 20 membered C4-20 cycloalkenyl, 4 to 20 membered C6-20 aryl and 5 to 20 membered heteroaryl; ring C is selected from the group consisting of 5 to 20 membered C6-20 aryl and heteroaryl; Ring D is selected from the group consisting of C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, 4- to 20-membered heterocycloalkenyl, C6-20 aryl, and 5- to 20-membered heteroaryl; ring E is selected from the group consisting of C3-20 cycloalkyl, 5- to 20-membered heterocycloalkyl,C6-20 aryl and heteroaryl groups of 5 to 20 members; L1 is selected from the group consisting of a single linkage, -N(Rb1)-, -N(Rb1)C(=O)HN >9 , -O-, -S-, -(CRb2Rb3)t-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and ; L2 is selected from the group consisting of a single linkage, -N(Rb1)-, -N(Rb1)C(=O)HN. / 9 , -O-, -S-, -(CRb2Rb3)t-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and ; Each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; alternatively, two Ri are connected together to form a cycloalkyl group. Petition 870250086442, 24 / 09 / 2025, p. 39 / 530 2 / 24 C3-20, 3- to 20-membered heterocycloalkyl,aril C6-20 or heteroaril of 5 to 20 members; J is I, and -¾ is 'R2; alternatively, Ί is 1, and R2 is R2; TT when Ί is H, T is C; T when H is । , T is selected from the group consisting of N and CH; '^R when 2 is R2, R2 is selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, SF5, CHO, COOH, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4 to 20 membered heterocycloalkenyl, C6-20 aryl and 5 to 20 membered heteroaryl, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, 3 to 20 membered heterocycloalkyl, C4-20 cycloalkenyl, heterocycloalkenyl from 4 to 20 members, C6-20 aryl and 5- to 20-membered heteroaryl groups are optionally replaced by 1, 2, or 3 R groups; when this is the case, R2 is selected from the group consisting of O and S; R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl.C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl groups of 3 to 20 members, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl groups of 3 to 20 members are optionally substituted by 1, 2 or 3 R; alternatively, R3 and R4 are linked together to form a C3-20 cycloalkyl or heterocycloalkyl group of 3 to 20 members, wherein the C3-20 cycloalkyl or heterocycloalkyl group of 3 to 20 members is optionally substituted by 1, 2 or 3 R; Each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, SF5, CN, Cho, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; alternatively, two R5 are connected together to form a C3-20 cycloalkyl group.3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, Petition 870250086442, dated 09 / 24 / 2025, p. 40 / 530 3 / 24 members, C6-20 aryl or 5- to 20-membered heteroaryl, wherein C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; Each R6 is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl, and 5- to 20-membered heteroaryl, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl, and 5- to 20-membered heteroaryl are optionally replaced by 1, 2, or 3 R; alternatively, two R6 are connected to each other to form a C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl, or 5- to 20-membered heteroaryl group.wherein C320 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; each R7 is independently selected from the group consisting of H, F, Cl, Br, OH, N(Rb4)2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; R8 is selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R; each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-20 alkyl, C1-20 heteroalkyl,C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R; Rb1 is selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, heterocycloalkyl of 3 to 20 members, C6-20 aryl and heteroaryl of 5 to 20 members, wherein C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, heterocycloalkyl of 3 to 20 members, C6-20 aryl and heteroaryl of 5 to 20 members are optionally replaced by 1, 2 or 3 R; Petition 870250086442, dated 24 / 09 / 2025, p. 41 / 530 4 / 24 Rb2 and Rb3 are each independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl and heterocycloalkyl of 3 to 20 members are optionally replaced by 1, 2 or 3 R; alternatively,Rb2 and Rb3 are linked together to form a 3- to 20-membered C3-20 cycloalkyl or heterocycloalkyl group; Rb4 is independently selected from the group consisting of H, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl are optionally replaced by 1, 2 or 3 R; m, n, p, qet are each independently selected from the group consisting of O, 1, 2 and 3; Each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, NH2, C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C6-20 aryl and 5- to 20-membered heteroaryl, wherein the C1-20 alkyl, C1-20 heteroalkyl, C3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl,C6-20 aryl and heteroaryl groups of 5 to 20 members are optionally replaced by 1, 2, or 3 R'; R' is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CH3CF3, C2H5, CN, SF5, Cho, COOH, and NH2; The C1-6 heteroalkyl, C1-20 heteroalkyl, 3- to 20-membered heterocycloalkyl, 4- to 20-membered heterocycloalkenyl, 5- to 20-membered heteroaryl, or 5- to 10-membered heteroaryl compound contains 1, 2, or 3 heteroatoms or groups of heteroatoms independently selected from the group consisting of -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2 and N.

2. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof, according to claim 1, characterized in that it satisfies one or more of the following: Petition 870250086442, dated 24 / 09 / 2025, p. 42 / 530 5 / 24 under the following conditions: (1) each R is independently selected from the group consisting of H,F, Cl, Br, Eu, -Vo OH, NH2, CN, SF5, CHO, COOH, NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino,-C1-6 alkyl-C1-6 alkoxy, -C1-6 alkyl-C1-6 alkylthium, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, -C(=O)-C1-6 alkyl, C1-6 alkyl-C(=6-C, -NH-C(=O)C1-6 alkyl, C1-6 alkyl-NH-C(=O)-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl, C1-6 alkyl-NH-S(=O)2C1-6 alkyl, C3-6 phenyl, naphthyl, pyridine, pyrilidine, pyrizinyl, pyrizinide, thienyl, pyrrolyl, pyrizolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiopyranyl, in which the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, alkyl-C1-6 alkylthium, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, -C(=O)C1-6 alkyl, C1-6 alkyl-C(=O)-C1-6 alkyl, -NH-C(=-O alkyl-NH-C(=O)-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl, C1-6 alkyl-NH-S(=O)2-C1-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine, pyryl, pyrizol, pyrizol imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl,furanyl, thiazolyl, oxazolyl and thiopyranil are optionally substituted by 1, 2 or 3 R';, (2) ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, tienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl and 1H-pyrrolyl, wherein phenyl, pyridyl, pyridazinyl, pyrimidinyl, tienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl and 1H-pyrrolyl are optionally replaced by 1, 2 or 3 Ra; (3) each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, Γ, \ C^”, — , and O , wherein Me, Λ, Γ , —° , * / N , , , O' , and *O-^ are optionally replaced by 1, 2 or 3 R; (4) when R2 is R2, R2 is selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, CHO, COOH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-6 cycloalkenyl, Petition 870250086442, dated 24 / 09 / 2025, p. 43 / 530 6 / 24 4- to 6-membered heterocycloalkenyl, C6-10 aryl and 5 to 10-membered heteroaryl, wherein C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-6 cycloalkenyl, 4- to 6-membered heterocycloalkenyl, C6-10 aryl and 5 to 10-membered heteroaryl are optionally substituted by 1, 2 or 3 R; (5) each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, -C1-6 alkyl-C1-6 alkoxy, -C1-6 alkyl-C1-6 alkylthio, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, C1-6 alkylC(=O)-, C1-6 alkyl-C(=O)-C1-6 alkyl, C1-6 alkyl-OC(=O)-, C1-6 alkyl-OC(=O)-C1-6 alkyl, NH-C(=O)-Ci-6 alkyl, C1-6 alkyl-NH-C(=O)-C1-6 alkyl, C1-6 alkyl-S(=O)2-, C1-6 alkylS(=O)2-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl, C1-6 alkyl-NH-S(=O)2-C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-S(=O)2-, and heterocycloalkyl of 3 to 6 members, in which C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, -C1-6 alkyl-C1-6 alkoxy, C1-6 alkyl-C1-6 alkylthio, -C1-6 alkyl-C1-6 alkylamino, C1-6 alkyl-OH, C1-6 alkyl-NH2, C1-6 alkyl-C(=O)-, C1-6 alkyl-C(=O)-C1-6 alkyl, C1-6 alkyl-OC(=O)-, C1-6 alkyl-OC(=O)-C1-6 alkyl, -NH-C(=O)-C1-6 alkyl, C1-6 alkyl-NH-C(=O)-C1-6 alkyl, C1-6 alkyl-S(=O)2-,C1-6 alkyl-S(=O)2-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl, C1-6 alkyl-NH-S(=O)2-C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloakyl-S(=O)2-, and the 3 to 6 membered heterocycloakyl are optionally substituted by 1, 2 or 3 R;, (6) ring B is selected from the group consisting of cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxinyl, 6-oxa3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyran-2-keto, phenyl, pyridyl, pyrrolidinyl, 2-oxa-6azaspiro[3.3]heptanyl, 1,1-dioxo-3,6-dihydro-2H-thiopyranyl, oxepinil, azetidinyl, 2-oxa-7azaspiro[4,4]nonanil and hexahydro-1H-furo[3,4-c]pyrrolyl; (7) each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, CHO, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl and C3-6 heterocycloalkyl are optionally replaced by 1, 2 or 3 R; alternatively, two R5 are connected together to form a C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl group, Petition 870250086442, 24 / 09 / 2025, p. 44 / 530 7 / 24 C6-10 aryl or heteroaryl of 5 to 10 members, wherein C3-6 cycloalkyl, heterocycloalkyl of 3 to 6 members, C4-10 cycloalkenyl, heterocycloalkenyl of 4 to 10 members, C6-10 aryl and heteroaryl of 5 to 10 members are optionally replaced by 1, 2 or 3 R; (8) ring C is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and tienyl; (9) each R6 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, L', / °, ^°, H / N , where Me or 3 R; HN-- / are optionally replaced by 1, 2 (10) ring D is selected from the group consisting of ; T1, T2, T3 and T4 are each independently selected from the group consisting of N and CH; X1, X2, X3 and X4 are each independently selected from the group consisting of a single bond and CH2; X5 and X6 are each independently selected from the group consisting of a single bond, CH2 and CH2CH2, and X5 and X6 are not simultaneously a single bond; X7, X8, X9 and X10 are each independently selected from the group consisting of a single bond, NH, O, S, CH2 and , and no more than four of X7, X8, X9 and X10 are simultaneously single bonds; La is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl and C1-6 heteroalkyl, wherein C1-6 alkyl and C1-6 heteroalkyl are optionally substituted by 1, 2 or 3 R; Petition 870250086442, dated 09 / 24 / 2025, p. 45 / 530 8 / 24 (11) each R7 is independently selected from the group consisting of H, F, Cl, Br, OH, z NH2, CN, Mer, / 0”,^0··, / ^·,»- / ^·^ , and O^ , where Me / , / °'',^°O z , O , ,□ , and 0 Z are optionally replaced by 1, 2 or 3 R; (12) ring E is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and tienyl; (13) R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me / , °'', ” , / N·, C^ -, ^'', O , and , wherein Me Γ , / , —° , *ζN , O , O , O , and O are optionally replaced by 1, 2 or R 3; (14) R8 is selected from the group consisting of H, Me, / , , , O , and □ I- Π'' 0 , wherein Me / , , 0 , I—I , and 0 are optionally replaced by 1, 2 or 3 R.

3. Compound, optical isomer or pharmaceutically acceptable salt thereof, according to claim 2, characterized in that it satisfies one or more of the following conditions: (1) each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, NH2, CH3, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I, 0 (2) ring A is selected from the group consisting of Ra , Ra , and Petition 870250086442, of 24 / 09 / 2025, p.46 / 530 9 / 24 (3) each Ra is independently selected from the group consisting of H, F, Cl, Br, OH, Λ” Γ~~ °” NH2, CN, Me,CF3, Γ, f , % f , Λ, · , % , -, Λ, l>, «Z, □ and Π / , and ; (4) when R2 is R2, R2 is selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, / , / , —° , * / N , > , 0 , and θ·^ , where Me, / , °” _y, and 0 are optionally replaced by 1, 2 or 3 R; (5) each Ri is independently selected from the group consisting of H, F, Cl, Br, OH, '\ ov λ ΛΛ Λ o \ 0 = SP FN— HO% \ o7 J o NH2, CN, Me Λ-, V , / , / , Λ , Ζ , , < , / (6) each R5 is independently selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, SF5, Me, CHO / , , where the °·· c Me / , / , _7 are optionally replaced by 1, 2 or 3 R; alternatively, two R5 are connected together to form IN-V « JN , or where Petition 870250086442, dated 24 / 09 / 2025, p.47 / 530 10 / 24 Q χΖ Q z H x H x V < i <Ni' <X' N R, N V N '', e são opcionalmente substituídos por 1, 2 ou 3 R; (7) cada Rô é independentemente selecionado do grupo que consiste em H, F, Cl, Br, OH, o— F— / ” F / 0-- n__ F“X ___ \|— NH2, CN, Me, CF3, γ, Λ , Λ , / , , f f , H / N , / , O-, o (8) cada R7 é independentemente selecionado do grupo que consiste em H, F, Cl, Br, OH, NH2, CN, Me, CF3 / , 0-1 Χο-Ά’,α', e (9) R3 e R4 são, cada um, independentemente selecionados do grupo que consiste em H, F \ 0-- o__ um___\ —Γ> F, Cl, Br, OH, NH2, CN, Me, cf3 A', F , ff , / ,.: : , HzN , / J>,0 F \ F^\ (10) Rs is selected from the group consisting of H, Me, CF3, <, F , FF , , οΓ>”,, and the 4. Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 2 or 3, characterized in that ring A is selected from the group consisting of --N Petition 870250086442, dated 24 / 09 / 2025, p.Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R2 is selected from the group consisting of H, F, Cl, Br, OH, NH2, CN, Me, CF3, / , f , ff , / 0-- / / F / f T- Λ O- □ e , ,, , ,,^ · 6. Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1 or 5, characterized in that the structural moiety , , , is selected from the group consisting of r2 r2 --NO --N / N' R0 IR ° N r2 Ra ' Ra O R2 Ra ' r2 oo Rs R2 Ra ' r2Ra o r2 oo Ra o r2 r2 , Λ XN n R2Ka I , R θ N XN r2 , Ra o NS Ra O r2 Ra ' r2 r2 x 1 , R0 ON r2 , and or wherein ring D is selected from the group consisting of Ou O, and OO 7. Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 6, characterized in that the structural fraction Petition 870250086442, dated 09 / 24 / 2025, p.49 / 530 12 / 24 is selected from the group consisting of oo 8. Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 2 or 3, characterized in that the structural fraction is selected from the group consisting of 9. Compound, optical isomer thereof or pharmaceutically acceptable salt thereof, according to claim 3, characterized in that each R5 is independently F— selected from the group consisting of H, F, Cl, Br, OH, NH2, SF5, CN, Me, CF3, CHOk , f FF O-- O-- O-- Op-- o__ fr( ft( fv( I ___ / FF Cl F Br F IF , , , , , HN- Petition 870250086442, dated 09 / 24 / 2025, page 50 / 530 Alternatively, two R5s are connected together to form '', , -, & or K &.