Smarca2 inhibitor, and preparation method therefor and use thereof

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry, and specifically relates to a fused-ring SMARCA2 inhibitor, and a preparation method therefor and the use thereof. The compound exhibits an excellent SMARCA2 inhibitory activity and can be used for treating SMARCA2-mediated diseases.

Description

SMARCA2 inhibitors, their preparation methods and uses

[0001] cross-references in applications

[0002] This application claims priority to Chinese patent applications 2024112174101 (filed August 30, 2024), 2024117725308 (filed December 2, 2024), 2025101148536 (filed January 23, 2025), 2025105582115 (filed April 28, 2025), and 202511187509.6 (filed August 22, 2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0003] This disclosure belongs to the field of medicinal chemistry, specifically relating to fused-ring SMARCA2 inhibitors, their preparation methods, and uses. These compounds exhibit excellent SMARCA2 inhibitory activity and can be used to treat SMARCA2-mediated diseases. Background Technology

[0004] The SWI / SNF complex consists of core subunits, catalytic subunits, and regulatory subunits, and includes three isotypes: the classic BRG1 / BRM-associated factor (cBAF), polybromo-associated BAF (PBAF), and the non-classical BAF (ncBAF). The core complex of all SWI / SNF CRC is composed of four core subunits: BAF155 (encoded by the SMARCC1 gene), BAF170 (encoded by the SMARCC2 gene), INI1 (SNF5 or BAF47, encoded by the SMARCB1 gene), and the ATPase subunits BRM (encoded by the SMARCA2 gene) / BRG1 (BRM / SWI2-associated gene 1, encoded by the SMARCA4 gene). SMARCA4 is mutated in a variety of tumors, including small cell ovarian cancer, urothelial carcinoma, non-small cell lung cancer, gastric cancer, sarcoma, melanoma, head and neck cancer, liver cancer, cervical cancer, and bile duct cancer. It is mutated in 10% of non-small cell lung cancer cells, and 50% of these SMARCA4 mutations are clearly loss-of-function mutations, which is higher than in other types of tumor cells.

[0005] SMARCA4 deletion mutations are highly correlated with poor differentiation in non-small cell lung cancer (NSCLC) tumors and are mutually exclusive with mutations in major NSCLC driver genes such as EGFR, ALK, RET, and ROS1. Therefore, patients with SMARCA4 deletions are unlikely to benefit from inhibitors targeting these mutations. However, 36% of NSCLC patients with SMARCA4 mutations also have KRAS mutations, and KRAS is also one of the major driver genes in some NSCLC patients. Under current targeted molecular therapies and tumor immunotherapies, the overall survival of NSCLC patients with homozygous deletion mutations of SMARCA4 is significantly worse than that of patients with heterozygous mutations of SMARCA4 and wild-type NSCLC. When SMARCA4 is inactivated, the expression level of SMARCA2 is compensatorily upregulated. The proliferation of tumor cells with homozygous deletion mutations of SMARCA4 is highly sensitive to SMARCA2 shRNAs, such as NCI-H838, NCI-H1299, and A549. However, SMARCA2 shRNA has little effect on wild-type SMARCA4 cells or cells with heterozygous SMARCA4 mutations, and does not affect the expression of other core SWI / SNF components. In vivo experiments also showed significant differences in the effects of SMARCA2 deletion on tumor growth in SMARCA4-mutant (NCI-H1299) and SMARCA4WT (NCI-H460) tumors. In SMARCA4-deficient NCI-H1299 tumors, SMARCA2 knockout led to a significant decrease in Ki67 (a proliferation marker), but no significant change was observed in SMARCA2WT tumors.

[0006] In summary, SMARCA2 and SMARCA4 have a clear synthetic lethal mechanism, and SMARCA2 / 4 inhibitors have shown significant toxicity to patients with hematologic malignancies in clinical trials. Therefore, there is a need to develop a SMARCA2 inhibitor with good selectivity to meet the clinical needs of patients with SMARCA4-mutant tumors. Summary of the Invention

[0007] This disclosure provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0008] Where W is C or N, and X1 is a chemical bond, N, O, S, =C(R) X1-1 - or -C(R) X1-2 )2-;

[0009] R4 exists or does not exist; when R4 exists, X2 is CH, C, or N; when R4 does not exist, X2 is CH, C, N, or O.

[0010] X3 is a chemical bond, -[CH(R) X3-1 )]m3 -、O、N(R X3-2 ), S, C 2-4 imide or C 2-4 Ethyne group;

[0011] X4 is a chemical bond, -[CH(R) X4-1 )] m4 -、O、N(R X4-2 ) or -SO2-;

[0012] X5 is a chemical bond, -[CH(R) X5-1 )] m5 -、O、N(R X5-2 ), S, -SO-, -SO2-, -SO(=N)-, -SO(R X5-3 )2-、-N=SO(R x5- 4) - or -C(O)-; where -N = SO(R) x5-4 The S atom of the )- group is attached to one end of the benzene ring;

[0013] X6 is -[CH(R) X6-1 )] m6 -N(R) X6-2 ) or O; where R X6-1 For H, CN, OH, NH2, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; R X6-2 For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl;

[0014] X9 can be CH2, CF2, O, NH, S or N(CH3);

[0015] R X1-1 R X1-2 R X3-1 R X3-2 R X4-1 R X4-2 R X5-1 R X5-2 R X5-3 R X5-4 Each is independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH or C 1-4 Alkyl-NH-CO-; or, one or two R X1-2 R X3-1 R X4-1 R X5-1 R X6-1 The atoms connected to it cyclize into 3-6 membered cycloalkanes;

[0016] R1 and R2 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or the atoms of R1, R2, and R2 cyclized to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, C 1-4 Alkoxy, C 1-4 Alkylthio, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl;

[0017] R3 and R4 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl Alternatively, R3, R4, X1, X2, and the atoms connected to them may cyclize together to form a 5-7 membered cycloalkane ring, a 5-7 membered heterocycloalkane ring, a 5-10 membered heteroaryl ring, or a 6-10 membered aryl ring. The cyclized 5-7 membered cycloalkane ring or 5-7 membered heterocycloalkane ring can be fused with other 3-6 membered cycloalkane or 3-6 membered heterocycloalkane rings to form a 4-10 membered spirocyclic ring or a 4-10 membered heterospirocyclic ring; the C 1-4Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-7 membered cycloalkane, 5-7 membered heterocycloalkane, 5-10 membered heteroaryl, and 6-10 membered aryl are optionally further substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1- 4-Haloalkoxy, hydroxy-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl;

[0018] R5 and R6 are independently designated as H and C in different regions. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy; or R5 co-cyclized with R3 and X1 to form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from the following: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl;

[0019] Y2 is O, S, or NH;

[0020] L1 is a -CONH-5-15-membered heteroaryl, 6-10-membered aryl, 5-15-membered heteroaryl, 6-13-membered cycloalkyl, or 6-13-membered heterocycloalkyl; wherein the 6-10-membered aryl, 5-15-membered heteroaryl, 6-13-membered cycloalkyl, and 6-13-membered heterocycloalkyl are optionally substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1- 4-alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl;

[0021] Or, R 1 Or R 2One of them co-cyclizes with L1 and its connected atoms to form a 5-7 membered cycloalkane ring or a 5-7 membered heterocycloalkane ring;

[0022] L2 is a chemical bond, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyneyl, 3-6 membered cycloeneyl, 3-6 membered heterocycloeneyl or 5-6 membered heteroaryl; the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The ynyl group, 3-6-membered cycloalkyl group, 3-6-membered heteroalkyl group, and 5-6-membered heteroaryl group are optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups;

[0023] L3 is a 6-10 aryl, 5-12 heteroaryl, 6-10 cycloalkyl, or 6-10 heterocycloalkyl;

[0024] R7 is a substituent of L3, selected from H, CN, OH, NH2, SF5, halogen, oxo, thio, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH, C 1-4 Alkyl-NH-CO- and The C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 The alkyl group -NH-CO- is optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4 Alkyl, C1-4 Haloalkyl, C 1- 4-alkoxy group, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 Alkyl-NH-CO-;

[0025] m1, m2, m3, m4, m5, and m6 are independently 0, 1, 2, 3, or 4;

[0026] n can be 0, 1, 2, 3 or 4 independently.

[0027] In one scheme of this disclosure I, two R X1-2 R X3-1 R X4-1 R X5-1 R X6-1 The atoms connected to it cyclize into 3-6 membered cycloalkanes.

[0028] In one embodiment of this disclosure I, L1 is a -CONH-5-15 heteroaryl group.

[0029] In one embodiment of this disclosure I, L2 is a 5-6 member heteroaryl group.

[0030] In one embodiment of this disclosure I, R 1 Or R 2 One of them co-cyclizes with L1 and the atoms connected to it to form a 5-7 membered cycloalkane ring or a 5-7 membered heterocycloalkane ring.

[0031] In one embodiment of this disclosure I, R7 is a 3-10 membered heterocyclic alkyl group.

[0032] In one embodiment of this disclosure I, the 3-10 membered heterocyclic alkyl group in R7 is a 3-8 membered cycloalkyl group.

[0033] In one embodiment of this disclosure I, L2 represents a chemical bond, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyneyl, 3-6 membered cycloalkylene, or 3-6 membered heteroalkylene; the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The ynyl group, 3-6 membered cycloalkyl group, and 3-6 membered heteroalkyl group may optionally be further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups.

[0034] In one embodiment of this disclosure I, R1 and R2 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or the atoms of R1, R2, and R2 cyclized to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, C 1-4 Alkylthio, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl.

[0035] In one embodiment of this disclosure I, R7 is a substituent of L3, selected from H, CN, OH, NH2, SF5, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH, C 1-4 Alkyl-NH-CO- and The C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 The alkyl group -NH-CO- is optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 Alkyl-NH-CO-.

[0036] In one embodiment of this disclosure I, it is a compound represented by formula Ia or formula Ib, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0037] In any of the schemes disclosed herein, in formula Ia, when R4 is present, X2 is CH or N; when R4 is absent, X2 is CH, N, or O.

[0038] In any of the embodiments disclosed herein, R3 and R4 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or Alternatively, R3, R4, X1, X2, and the atoms connected to them may cyclize together to form a 5-7 membered cycloalkane ring, a 5-7 membered heterocycloalkane ring, or a 5-10 membered heteroaromatic ring. The cyclized 5-7 membered cycloalkane ring or 5-7 membered heterocycloalkane ring can be fused with other 3-6 membered cycloalkane or 3-6 membered heterocycloalkane rings to form a 4-10 membered spirocyclic ring or a 4-10 membered heterospirocyclic ring; the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-7 membered cycloalkane, 5-7 membered heterocycloalkane, and 5-10 membered heteroaromatic rings may optionally be further substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl.

[0039] In one embodiment of this disclosure, X1 is a chemical bond.

[0040] In one embodiment of this disclosure, R3 and R4 are each independently H, halogen, or C. 1-4Alkyl groups, such as H, F, Cl, Br, or CH3.

[0041] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms connected thereto are cyclized together to form a 5-7 membered cycloalkane ring, a 5-7 membered heterocycloalkane ring, or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-7 membered heterocycloalkane ring and the 5-10 membered heteroaryl group are each selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; wherein the 5-7 membered cycloalkane ring, the 5-7 membered heterocycloalkane ring, and the 5-10 membered heteroaryl group are optionally substituted by one or more groups selected from the following groups: halogen and C. 1-4 Alkyl substitution.

[0042] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms attached to them can co-cyclize into a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic alkyl ring; wherein the 5-6 membered heteroaromatic ring and the 5-6 membered heterocyclic alkyl ring are optionally substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-8 membered cycloalkyl group and 3-8 membered heterocycloalkyl group.

[0043] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms they are attached to can co-cyclize into a 5-6 membered heteroaromatic ring, wherein the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1-3. The 5-6 membered heteroaromatic ring is optionally oxidized by one or more halogens or C. 1-4 Alkyl substitution, preferably by one or more halogens.

[0044] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms they are attached to can co-cyclize into a 5-membered heteroaryl ring, wherein the heteroatom is N, and the number of heteroatoms is 2 or 3. The 5-membered heteroaryl ring is optionally coated with one or more halogens or carbon atoms. 1-4 Alkyl substitution, preferably by one or more halogens.

[0045] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms they are connected to can co-circulate into a ring. It is optionally substituted by one or more groups selected from the following groups: halogen and C 1-4 Alkyl substitution.

[0046] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms they are connected to can co-circulate into a ring.

[0047] In one embodiment of this disclosure, R3, R4, X1, X2, and the atoms they are connected to can co-circulate into a ring.

[0048] In one embodiment of this disclosure, W is C.

[0049] In one embodiment of this disclosure, W is N.

[0050] In any of the schemes of this disclosure Ia, for Where X7 represents chemical bonds, O, N, S, =C(R) X7-1 )-、-C(R X7-2 )2- or N(R X7-3 X8 represents chemical bonds, O, N, S, =C(R) X8-1 )-、-C(R X8-2 )2- or N(R X8-3 ); R X7- 1. R X7-2 R X7-3 R X8-1 R X8-2 R X8-3 Each independently constitutes a chemical bond, H, CN, OH, NH2, halogen, and C. 1-4 Alkyl, C 1- 4-Haloalkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or two R X7-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or two R X8-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or R X7-2 R X8-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 5-10 membered heteroaryl. X1, X2, X3, X4, X5, and X9 have the same meaning as in any scheme of Formula I.

[0051] In one of the schemes, X1 is N, = C(R) X1-1 )-、-C(R X1-1 )2-, S or O; X2 is N or CH; X7 is =C(R) X7-1 )-、-C(R X7-2 X2- or N; X8 is a chemical bond or CH2; X9 is O or CH2.

[0052] In another scheme, X1 is N, =CH-, =CF-, -CH2-, S or O; X2 is N or CH; X7 is =CH-, =CF-, -CH2-, N or O; X8 is a chemical bond or CH2; X9 is O or CH2.

[0053] In this disclosed scheme, X8 is a chemical bond.

[0054] In any of the schemes of this disclosure Ia, for X1, X2, X3, X4, X5, and X9 have the same meaning in any of the schemes in Equation I. In one scheme, X1 is 0 and X2 is N.

[0055] In any of the schemes of this disclosure I, for X1, X2, X3, X4, X5, X7, and X9 have the same meaning as in any scheme of Equation I.

[0056] In any of the schemes of this disclosure I, for X1, X2, X3, X4, X5, X7, and X9 have the same meaning as in any scheme of Equation I.

[0057] In any of the schemes disclosed herein, X1 is N or = C(R) X1-1 )-;R X1-1 H, halogen or C 1-4 Alkyl group, preferably halogen (e.g., F, Cl, Br or I). X1 is preferably N, =CH-, =CCH3- or =CF-, more preferably N or =CF-.

[0058] In any scheme of this disclosure I, X2 is N or CH.

[0059] In any of the schemes disclosed herein, X2 is N.

[0060] In any of the schemes disclosed herein, X3 is -[CH(R X3-1 )] m3 -、O or N(R) X3-2 ); R X3-1 and R X3-2 Each is independently H, halogen, or C 1-4Alkyl group, preferably H; m3 is 1 or 2.

[0061] In any of the embodiments disclosed herein, X3 is -CH2- or -CH2CH2-.

[0062] In any embodiment of this disclosure I, X4 is a chemical bond, CHR X4-1 、N(R X4-2 ) or O; the R X4-1 H, halogen, C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups, preferably H, F, Cl, Br, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, or trifluoromethoxy; or R X4-1 The atoms commonly bonded to it cyclize together to form cyclopropyl or cyclobutyl groups; the R X4-2 For H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, preferably H, methyl or ethyl.

[0063] In any of the embodiments disclosed herein, X4 is CHR. X4-1 R X4-1 H, halogen or C 1-4 Alkyl groups, preferably H, F, Cl, Br, methyl or ethyl.

[0064] In any of the embodiments disclosed herein, X4 is CHR. X4-1 R X4-1 Each element is independently a halogen, preferably F, Cl, or Br. In any embodiment of Formula I, X4 is a chemical bond, CH2, CHF, NH, or N(CH3).

[0065] In any embodiment of this disclosure, X4 is CH2.

[0066] In any of the schemes disclosed herein, X4 is CHF.

[0067] In any of the schemes disclosed herein, R X4-1 The atoms that are connected to it cyclize into cyclopropyl groups.

[0068] In any of the embodiments disclosed herein, X5 is a chemical bond, -SO2-, -SO(=N)-, -SO(CH3)2- or -N=SO(CH3)-, wherein the S atom of -N=SO(CH3)- is connected to a benzene ring at one end.

[0069] In any of the schemes disclosed herein, X5 is -SO2-, -SO(=N)-, or -N=SO(CH3)-.

[0070] In any of the schemes disclosed herein, X5 is -SO2-.

[0071] In any of the schemes disclosed herein, X7 is N or = C(R) X7-1 )-;R X7-1 H, halogen or C 1-4 Alkyl groups, preferably H, F, Cl, Br, methyl, or ethyl. More preferably H, F, or methyl.

[0072] In any of the schemes disclosed herein, X7 is = C(R) X7-1 )-;R X7-1 The halogen is preferred, with F, Cl, and Br being the most suitable.

[0073] In any of the schemes disclosed herein, X7 is = C(R) X7-1 )-;R X7-1 C 1-4 Alkyl, preferably methyl or ethyl.

[0074] In any of the schemes disclosed herein, X7 is N.

[0075] In any of the schemes disclosed herein, X7 is =CH-.

[0076] In any of the schemes disclosed herein, X7 is =CF-.

[0077] In any embodiment of this disclosure, X7 is =CCH3-.

[0078] In any embodiment of this disclosure, X9 is CH2 or O.

[0079] In any embodiment of this disclosure, X9 is CH2.

[0080] In any of the embodiments disclosed herein, X4 is a chemical bond and X5 is -N=SO(CH3)-, wherein one end of the S atom of -N=SO(CH3)- is connected to the benzene ring.

[0081] In any embodiment of this disclosure I, X2 is N or CH; X3 is O or CH. 2； X4 is NH, N(CH3) or CH2; X5 is -SO2-, -SO(=N)- or -N=SO(CH3)-.

[0082] In any scheme of this disclosure I, X2 is N or CH, X3 is CH2, X4 is CH2, and X5 is -SO2-.

[0083] In any embodiment of this disclosure I, R5 and R6 are both H.

[0084] In one embodiment of this disclosure Ia, It can be Among them, R X1-1 R X1- 2. R X7-1 R X7-2 R X8-2 R3, X1, X3, X4, X9 are as defined in any of the schemes disclosed herein, and X5 is -SO2- or a chemical bond.

[0085] In one embodiment of this disclosure Ia, It can be Among them, R X1-1 R X1-2 R X7-1 R X7-2 R X8-2 R3, X1, X3, X4, X9 are as defined in any of the schemes disclosed herein, and X5 is -SO2- or a chemical bond.

[0086] In one embodiment of this disclosure Ia, It can be Among them, R X1-1 R X1-2 R X7-1 R X7-2 R X8-2 R3, X1, X3, X4, X9 are as defined in any of the schemes disclosed herein, and X5 is -SO2- or a chemical bond.

[0087] In one embodiment of this disclosure Ia, It can be Among them, R X1-1 R X1-2 R X7-1 R X7-2 R X8-2 R3, X1, X3, X4, X9 are as defined in any of the schemes disclosed herein, and X5 is -SO2- or a chemical bond.

[0088] In one of the disclosed solutions, It can be Among them, R X1-1 X3, X4, and X9 are as defined in any of the embodiments disclosed herein.

[0089] In one of the disclosed solutions, It can be Among them, R X1-1X3, X4, and X9 are as defined in any of the embodiments disclosed herein.

[0090] In one of the disclosed solutions, It can be X3, X4, and X9 are as defined in any of the schemes disclosed herein.

[0091] In any of the schemes of this disclosure Ia, for

[0092] In any of the schemes of this disclosure Ia, for

[0093] In any of the schemes of this disclosure Ia, for

[0094] In one of the disclosed solutions, for

[0095] In one of the disclosed solutions, for

[0096] In one of the disclosed solutions, for

[0097] In one of the disclosed solutions, for

[0098] In one of the disclosed solutions, for

[0099] In any of the solutions disclosed herein, for

[0100] In any of the solutions disclosed herein, for

[0101] In any of the solutions disclosed herein, for

[0102] In any of the schemes disclosed herein, Y2 is NH.

[0103] In any of the schemes disclosed herein, Y2 is 0.

[0104] In any of the schemes disclosed herein, X6 is N(R) X6-1 ), R X6-1 H and C independently 1-4 Alkyl or C 1-4 Halogenated alkyl groups, preferably H or C 1-4 Alkyl group; in one embodiment, X6 is NH or N(CH3).

[0105] In any embodiment of this disclosure, X6 is NH.

[0106] In any embodiment of this disclosure, X6 is N(CH3).

[0107] In any of the embodiments disclosed herein, R1 and R2 are independently H, OH, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy-C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0108] In any of the embodiments disclosed herein, R1 and R2 are independently H, OH, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl or 3-6 heterocyclic alkyl.

[0109] In any of the schemes disclosed herein, R1 and R2 are both H.

[0110] In any embodiment of this disclosure, R1 is methyl or ethyl, and R2 is H.

[0111] In any of the embodiments disclosed herein, R1 is methyl, methoxymethyl, methoxyethyl, ethoxymethyl, trifluoromethyl, trifluoromethoxy, or 2,2,2-trifluoroethoxy, and R2 is H.

[0112] In any embodiment of this disclosure, R1, R2, and the atoms they are attached to are cyclized together to form a cyclopropyl or cyclobutyl group; said cyclopropyl or cyclobutyl group is optionally further substituted by one or more groups selected from the following: CN, F, Cl, NH2, OH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and hydroxy-C1-4 alkyl.

[0113] In any embodiment of this disclosure, R1, R2 and the atoms they are connected to are cyclized together to form a cyclopropyl group.

[0114] In any of the embodiments disclosed herein, L1 is a -CONH-5-15-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0115] In any of the embodiments disclosed herein, L1 is a -CONH-5-membered heteroaryl group.

[0116] In any of the schemes disclosed herein, L1 is

[0117] In any of the embodiments disclosed herein, L1 is a 6-10 aryl or a 5-10 heteroaryl.

[0118] In any of the embodiments disclosed herein, L1 is a 10-15 member heteroaryl group.

[0119] In any of the embodiments disclosed herein, L1 is a 10-15 member heteroaryl group that is either bicyclic or tricyclic.

[0120] In any of the embodiments disclosed herein, L1 is a bicyclic 10-membered heteroaryl group.

[0121] In any of the embodiments disclosed herein, L1 is a tricyclic 11-14 member heteroaryl group.

[0122] In any of the schemes disclosed herein, L1 is Among them, R L1 Each of these elements independently represents H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or hydroxy-C 1-4 Alkyl group; q is 0, 1, 2 or 3.

[0123] In one of the schemes, R L1 It can be H, F, Cl, methyl, or ethyl.

[0124] In any of the schemes disclosed herein, R L1 It is H or a halogen, preferably H, F or Cl.

[0125] In any scheme disclosed herein, q is 0 or 1.

[0126] In any of the schemes disclosed herein, L1 is

[0127] In any of the schemes disclosed herein, L1 is

[0128] In any of the schemes disclosed herein, L1 is Among them, R L1 CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or hydroxy-C 1-4 Alkyl group; q is 0, 1, 2 or 3.

[0129] In any of the schemes disclosed herein, L1 is One end marked with an asterisk (*) is connected to the L2 or L3 side.

[0130] In any of the schemes disclosed herein, L1 is One end marked with an asterisk (*) is connected to the L2 or L3 side.

[0131] In any of the schemes disclosed herein, L1 is One end marked with an asterisk (*) is connected to the L2 or L3 side.

[0132] In any of the schemes disclosed herein, L1 is One end marked with an asterisk (*) is connected to the L2 or L3 side.

[0133] In any of the embodiments disclosed herein, L2 represents a chemical bond, C 1-4 Alkylene, C 1-4 imidene group, C 1-4 The group is alkynyl, 3-6-membered cycloalkylene, 3-6-membered heteroalkylene, or 5-6-membered heteroaryl, and optionally substituted with one or more groups selected from: CN, halogen, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0134] In any of the embodiments disclosed herein, L2 represents a chemical bond, C 1-4 Alkylene, C 1-4 imidene group, C 1-4 The group is alkynyl, 3-6 membered cycloalkylene, or 3-6 membered heteroalkylene, and optionally substituted with one or more groups selected from: CN, halogen, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0135] In any of the embodiments disclosed herein, L2 represents a chemical bond, C1-4 Alkylene, C 1-4 imidene group, C 1-4 Alynyl, 3-6 membered cycloalkyl or 3-6 membered heteroalkyl.

[0136] In any embodiment of this disclosure, L2 represents a chemical bond, ethylidene, vinylidene, ethynylidene, cyclobutane, or alkylene.

[0137] In any embodiment of this disclosure, L2 is a chemical bond, ethylene, vinylene, ethynylene, or cyclobutane.

[0138] In any embodiment of this disclosure, L2 is a chemical bond, 1-fluoro-ethylidene, vinylidene, ethynylidene, or cyclobutane.

[0139] In any of the embodiments disclosed herein, L2 is a chemical bond.

[0140] In any embodiment of this disclosure, L2 is vinylene or ethynene.

[0141] In any embodiment of this disclosure, L2 is a vinylene and is optionally substituted with one or more halogens.

[0142] In any scheme of this disclosure, L2 is -CF = CH-.

[0143] In any of the schemes disclosed herein, L3 is a 6-membered aryl, a 5-6-membered monocyclic heteroaryl, or a 6-10-membered bicyclic heteroaryl.

[0144] In any scheme of this disclosure I, L3 is pyridine, In this embodiment, A1, A2, and A3 are each independently a chemical bond, CH2, O, S, NH, or -C(=O)-, preferably CH2, O, S, or NH; A4 is N or CH; A5, A6, and A7 are each independently a chemical bond, N or CH, preferably N or CH; A8 is CH2, S, or O. In one embodiment, A1 is O, A2 and A3 are both CH2, and A4 is N or CH. In any embodiment of this disclosure I, L3 is pyridine, In this configuration, A1, A2, and A3 are each independently a chemical bond, CH2, O, S, or NH, preferably CH2, O, S, or NH; A4 is N or CH; A5, A6, and A7 are each independently a chemical bond, N or CH, preferably N or CH; and A8 is CH2, S, or O. In one embodiment, A1 is O, A2 and A3 are both CH2, and A4 is N or CH.

[0145] In any embodiment of this disclosure I, L3 is pyridine or In this scheme, A1, A2, and A3 are each independently CH2, O, S, or NH; A4 is N or CH; and A5, A6, and A7 are each independently N or CH. In one scheme, A1 is O, A2 and A3 are both CH2, and A4 is N or CH.

[0146] In any scheme of this disclosure I, L3 is

[0147] In any scheme of this disclosure I, L3 is

[0148] In any scheme of this disclosure I, L3 is pyridine,

[0149] In any of the embodiments disclosed herein, L3 is pyridine,

[0150] In any of the schemes disclosed herein, L3 is

[0151] In any embodiment of this disclosure, -L1-L2- are the following groups: The end marked with an asterisk (*) is connected to the L3 side.

[0152] In any embodiment of this disclosure, -L1-L2- are the following groups: The end marked with an asterisk (*) is connected to the L3 side.

[0153] In any embodiment of this disclosure, -L1-L2- are the following groups: The end marked with an asterisk (*) is connected to the L3 side.

[0154] In any embodiment of this disclosure, -L1-L2-L3 are the following groups: Among the markings One end is L1 side.

[0155] In any embodiment of this disclosure, -L1-L2-L3 are the following groups: Among the markings One end is L1 side.

[0156] In any embodiment of this disclosure, -L1-L2-L3- are the following groups: Among the markings One end is L1 side.

[0157] In any embodiment of this disclosure, -L1-L2-L3- are the following groups: Among the markings One end is L1 side.

[0158] In any of the schemes disclosed herein, -L1-L2-L3- is

[0159] In any embodiment of this disclosure, R7 is a substituent for L3, selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, or 5-10-membered heteroaryl; wherein the 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, or 5-10-membered heteroaryl is optionally further substituted by one or more groups selected from: OH, oxo, halogen, C 1-4 Alkyl or C 1-4 Alkyl group.

[0160] In any scheme disclosed herein, n is 1 or 2.

[0161] In any of the embodiments disclosed herein, R7 is F, methyl, oxo, thio, cyclopropyl, 3,5-dimethyl-morpholino-1-yl, difluoromethyl, 1,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, methoxyethyl,

[0162] In any of the embodiments disclosed herein, R7 is F, methyl, oxo, thio, cyclopropyl, 3,5-dimethyl-morpholino-1-yl, difluoromethyl, 1,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, methoxyethyl,

[0163] In any of the embodiments disclosed herein, R7 is F, methyl, cyclopropyl, 3,5-dimethyl-morpholin-1-yl, difluoromethyl, 1,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy,

[0164] In any of the embodiments disclosed herein, R7 is cyclopropyl, 3,5-dimethylmorpholino-1-yl, difluoromethyl, 1,2,2-trifluoroethyl, methoxy, ethoxy, or

[0165] In any embodiment of this disclosure, R7 is 3,5-dimethyl-morpholin-1-yl. In any embodiment of this disclosure, -L3-(R7) n It includes the following groups:

[0166] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0167] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0168] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0169] In any of the schemes disclosed herein, -L3-(R7) n for In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0170] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0171] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0172] In any of the schemes disclosed herein, -L3-(R7) n It includes the following groups:

[0173] In one embodiment of this disclosure I, for And / or L1 is a pyridine or tricyclic 11-14 membered heteroaryl group; and / or R7 is And / or R3-X1- is F, Cl or

[0174] In one embodiment of this disclosure I, the compound is represented by Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0175] Among them, R1, R2, R X6-1 R1, R2, R3, R4, X5, X9, and n are as defined in any of the embodiments disclosed herein. In one embodiment, R1 and R2 are both H, or R1, R2, and the atoms to which they are attached are cyclopropylated; R X6-1 H; R7 and n are defined in any scheme of this disclosure.

[0176] In one embodiment of this disclosure I, the compound is a compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0177] Among them, R1, R2, R X1-1 R X6-1 R1, R2, R3, R4, R9, R3, and Rn are as defined in any of the embodiments disclosed herein. In one embodiment, R1 and R2 are both H, or R1 and R2 are cyclized with the atoms attached to them to form cyclopropyl groups; R X6-1 H; R7 and n are defined in any scheme of this disclosure.

[0178] In one embodiment of this disclosure I, the compound is a compound of formula IV, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0179] Among them, R1, R2, R X1-1 R X6-1 R L1 R1, R2, R3, R4, R9, R3, Rn, and Rq are as defined in any of the embodiments disclosed herein. In one embodiment, R1 and R2 are both H, or R1 and R2 are cyclized with the atoms attached to them to form cyclopropyl groups; R X6-1 H; R7 and n are defined in any scheme of this disclosure.

[0180] In one embodiment of this disclosure I, the compound is a compound of formula IV-1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0181] Among them, R1, R2, R X1-1 R X6-1 R L1 R1, R2, R3, R4, R9, n, and q are as defined in any of the embodiments disclosed herein. In one embodiment, R1 and R2 are both H, or R1 and R2 are cyclized with the atoms they are attached to to form cyclopropyl groups; R X6-1 H; R7 and n are defined in any scheme of this disclosure.

[0182] In the scheme of this disclosure I, it is the following compound, its pharmaceutically acceptable salt, or its stereoisomer:

[0183] A second aspect of this disclosure provides a pharmaceutical composition comprising the compound described in the first aspect of this disclosure or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and any pharmaceutically acceptable carrier. In some embodiments of this disclosure, the pharmaceutical composition contains 0.1 mg to 1000 mg of the compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition contains 1000 to 2000 mg of the compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier in the pharmaceutical composition comprises one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0184] This third aspect of the disclosure provides the use of the compounds described in the first aspect of the disclosure, pharmaceutically acceptable salts thereof, or stereoisomers thereof, in the preparation of a medicament for treating diseases associated with mutations in the SMARCA2 and / or SMARCA4 genes.

[0185] In one embodiment, the use of the compound described in the first aspect of this disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for treating diseases associated with SMARCA4 gene mutations is provided.

[0186] This fourth aspect of the disclosure provides the use of the pharmaceutical composition described in the second aspect of the disclosure in the preparation of a medicament for treating diseases associated with mutations in the SMARCA2 and / or SMARCA4 genes.

[0187] In one embodiment, the use of the pharmaceutical composition described in the second aspect of this disclosure in the preparation of a medicament for treating diseases associated with SMARCA4 gene mutations is provided.

[0188] The fifth aspect of this disclosure provides a method for treating diseases associated with mutations in the SMARCA2 and / or SMARCA4 genes, the method comprising administering to a patient in need an effective amount of the compound described in the first aspect of this disclosure, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition described in the second aspect of this disclosure.

[0189] One approach provides a method for treating a disease associated with a SMARCA4 gene mutation, the method comprising administering to a patient in need an effective amount of the compound described in the first aspect of this disclosure, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition described in the second aspect of this disclosure.

[0190] In this disclosure, the diseases associated with SMARCA2 and / or SMARCA4 gene mutations may be ovarian cancer, urothelial carcinoma, non-small cell lung cancer, gastric cancer, sarcoma, melanoma, head and neck cancer, liver cancer, cervical cancer, or bile duct cancer associated with SMARCA2 and / or SMARCA4 gene mutations.

[0191] In one embodiment, the disease associated with SMARCA4 gene mutation can be ovarian cancer, urothelial carcinoma, non-small cell lung cancer, gastric cancer, sarcoma, melanoma, head and neck cancer, liver cancer, cervical cancer, or bile duct cancer associated with SMARCA4 gene mutation.

[0192] Technical effect

[0193] These compounds possess excellent SMARCA2 enzyme and cell inhibitory activity, and can be used to treat SMARCA2-mediated diseases. Attached Figure Description

[0194] Figure 1 shows the weight changes in A549 xenograft lung cancer model mice after administration of compound 31A.

[0195] Figure 2 shows the tumor growth curves of A549 xenograft lung cancer model mice after administration of compound 31A.

[0196] Figure 3 shows the changes in body weight in the RERF-LC-A1 human lung cancer xenograft model mice after administration of compounds 31A and 50.

[0197] Figure 4 shows the tumor growth curves of RERF-LC-A1 human lung cancer xenograft model mice after administration of compounds 31A and 50.

[0198] Definitions and Explanations

[0199] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0200] In the embodiments of this disclosure, when using supercritical fluid chromatography to separate chiral compounds, unless otherwise specified, the fluid is carbon dioxide and a modified solvent.

[0201] In this disclosure, if a variable is a chemical bond, it can be understood as the variable not existing, and two variables that were originally indirectly connected through this variable will be directly connected. For example, for R3-X1-Ar, when X1 is a chemical bond, it is equivalent to R3–Ar.

[0202] In this disclosure, if two adjacent substituents or segments are cyclized into a new ring, when the resulting ring is a cycloalkyl or heterocycloalkyl ring, it means that the unsaturated bonds on the common edges of the resulting new ring and other rings are not included in the new ring; when the resulting ring is an aryl or heteroaryl ring, it means that the unsaturated bonds on the common edges of the resulting ring and other rings are included in the new ring.

[0203] In this disclosure, if the chemical structural formula or general chemical formula contains... When the position is indicated, it indicates whether the chemical bond at that position is a single bond or a double bond; the specific type of chemical bond in a particular situation is determined by the specific valence of the atoms connected to both ends of the chemical bond.

[0204] In this disclosure, H refers to the element hydrogen or an atom of that element, i.e., an atom with a proton number or nuclear charge of 1. Hydrogen atoms can be further classified into three types of nuclei based on the number of neutrons in their nuclei: protium (P), deuterium, and tritium.

[0205] In this disclosure, the term "oxo" refers to the =O structure being attached as a substituent to other structures.

[0206] In this disclosure, the term "thiolated" refers to the =S structure being attached as a substituent to other structures.

[0207] In this disclosure, the term "alkylthio" means alkyl-S-, referring to a group obtained by substituting a thiol group (-SH) with an alkyl group. 1-4 Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and n-butylthio.

[0208] The term "isotope derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes in the compounds disclosed herein include, but are not limited to, isotopes of hydrogen (e.g., deuterium (2H), tritium (3H)); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S). Isotope-labeled compounds of this disclosure can generally be prepared using common techniques known to those skilled in the art, or can be prepared using a suitable isotope-labeling reagent instead of an unlabeled reagent, in a manner similar to that described herein.

[0209] The term "solvent compound" refers to an association or complex of one or more solvent molecules with a compound disclosed herein. The term "hydrate" may be used when the solvent is water. The solvent molecules may be stoichiometric or non-stoichiometric. Methods for preparing solvates are known in the art.

[0210] The term "nitrogen oxide" or "N-oxide" refers to derivatives formed by the further oxidation of nitrogen atoms in nitrogen-containing groups. Common N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. Methods for synthesizing N-oxides are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid, hydrogen peroxide, alkyl hydrogen peroxides such as tert-butyl hydrogen peroxide, sodium perborate, and diethylene oxides such as dimethyldiethylene oxide.

[0211] The disclosed compounds and their salts may exist in the form of isotopic derivatives, and the disclosed compounds include various isotopic derivatives and mixtures thereof.

[0212] The compounds disclosed herein and their salts may exist in the form of solvates, such as hydrates, and the compounds disclosed herein include various solvates and mixtures thereof.

[0213] The disclosed compounds and their salts may exist in the form of "N-oxides", and the disclosed compounds include various N-oxides and mixtures thereof.

[0214] The compounds described in this disclosure, their pharmaceutically acceptable salts, isotope derivatives, solvates, and N-oxides having the same or similar biological activities are all included within the scope of this disclosure.

[0215] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0216] The term "effective dose" refers to a sufficient amount of the disclosed compound, its pharmaceutically acceptable salt, or its stereoisomer to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dosage of the disclosed compound, its stereoisomer, its pharmaceutically acceptable salt, and the composition thereof must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific therapeutically effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0217] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis can be used to confirm the absolute configuration. Alternatively, after resolution, the stereoconfiguration can be determined by comparison with a product whose absolute configuration is known. Compounds marked as "absolute configuration unknown / undetermined" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0218] The term “optionally” means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility. For example, the term “optionally substituted by one or more Rs” means that it may or may not be substituted by one or more Rs.

[0219] When any variable (e.g., R1) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, it means that pyridine is replaced by x R1s, and each R1 has an independent option.

[0220] When a substituent is chemically bonded non-limitingly to a monocyclic or fused ring, it can bond to any atom on that ring. For example, structural units. This indicates that the substituent R1 can be substituted at any position on the pyridine; structural unit This indicates that the substituent RL1 can retroactively substitute for any atom on the tricyclic fused ring.

[0221] When the listed substituents do not specify which atom they are attached to in a compound included but not specifically mentioned in the general chemical formula, such substituents can be bonded to any of their atoms. For example, pyrimidine as a substituent means that any carbon or nitrogen atom on the pyrimidine ring is attached to the substituted group; when the structure contains... When, it indicates that the atom is a bonding atom, for example This indicates that the C atom at the 3-position of pyridine is a bonding atom.

[0222] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1-4 "Alkyl" refers to an alkyl group comprising 1 to 4 carbon atoms. 1-4 Specific examples of "alkyl" include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.

[0223] Unless otherwise specified, the term "alkylene" refers to a substituent derived from an alkane by the loss of two hydrogen atoms. 1-4 Examples of alkylene groups include, but are limited to: methylene (-CH2-), ethylene (-CH2-CH2-), and n-propylene (-CH2-CH2-CH2-).

[0224] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched olefin (containing at least one carbon-carbon double bond) by removing one hydrogen atom, including methanyl, "C" and "H" groups. 2-6 "alkenyl", "C" 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", C 2-4 Specific examples of alkenyl groups include, but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc. The methanyl group refers to an alkylene group bonded to the same atom in the form of a double bond, which can be represented as CH2=.

[0225] Unless otherwise specified, the term "alkenyl" refers to a substituent formed when an alkene loses two hydrogen atoms. 1-4 Examples of alkenyl groups include, but are not limited to: vinylidene (-CH=CH-) and propenylidene (-CH=CH-CH2-).

[0226] Unless otherwise specified, the term "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing one hydrogen atom, including "C". 2-6 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alkyne", C1-4 Specific examples of alkynyl groups include, but are not limited to: ethynyl (-C≡CH) and propynyl (-C≡CHCH). 3) Butynyl (CH3-CH2-C≡C-), etc.

[0227] Unless otherwise specified, the term "ethynyl" refers to a substituent formed by the loss of two hydrogen atoms from an ethynyl group. 1-4 Examples of ynylene groups include, but are not limited to: ynylene (-C≡C-), ynylene (-C≡C-CH2-), and ynylene diynylene (-C≡CC≡C-).

[0228] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-3 Alkoxy, C 1-4 Specific examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, etc.; preferably, the "alkoxy group" described in this disclosure is preferably C. 1-3 Alkyl group.

[0229] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0230] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3 Alkyl halogens. Examples of alkyl halogens include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0231] Unless otherwise specified, the term "hydroxy-alkyl" refers to a substituent derived from an alkyl group in which one or more H atoms are replaced by a hydroxyl group. The term "hydroxyalkyl" as used in this disclosure includes "hydroxy-C..." 1-6 "hydroxyalkyl", "hydroxy-C" 1-4 Alkyl group; hydroxyl group - C 1-4 Specific examples of alkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -CH2CH2CH2OH.

[0232] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-3Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0233] Unless otherwise specified, the term “heteroatom” refers to a substituted or unsubstituted heteroatom and its oxidized form (also called a heterogroup), which is generally selected from N, O, and S, and whose oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein). The number of atoms on the ring is usually defined as the ring number, for example, “3-6 membered heterocyclic alkyl” refers to a ring of 3-6 atoms arranged in a ring, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, CO, S, NO, SO, S(O)2, or NR, each ring optionally substituted by an R group, R being a group defined herein.

[0234] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fused, or other means. The carbon atom in the cycloalkyl group may be further oxidized, i.e., forming C(O). Unless otherwise specified, "membered cycloalkyl" as used herein can be understood as a monocyclic cycloalkyl group, and when it is polycyclic, it will be specifically specified as a spiro, fused, or bridged ring group. Specific examples of 3-6 membered cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0235] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated cyclic group derived from which one or more carbon atoms in a cycloalkyl group are replaced by heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from N, O, S, NO, SO, S(O)₂, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1 to 3 N and / or O atoms. Heterocyclic alkyl groups include "3-12-membered heterocyclic alkyl", "3-8-membered heterocyclic alkyl", "3-6-membered heterocyclic alkyl", "3-5-membered heterocyclic alkyl", "4-6-membered heterocyclic alkyl", and "5-6-membered heterocyclic alkyl". Examples of 3-6-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, N-heterocyclic butyl, morpholino, and N-heterocyclic pentane.

[0236] Unless otherwise specified, the term "heterospirocyclic group" refers to a spirocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from N, S, and O.

[0237] Unless otherwise specified, the term "aryl" refers to an unsaturated, aromatic cyclic hydrocarbon group, which may be monocyclic or polycyclic, but with at least one aromatic ring. The aryl group may be fused to a heterocyclic alkenyl or cycloalkenyl group. 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0238] The term "heteroaryl" as used in this disclosure refers to a monocyclic or polycyclic hydrocarbon group that is aromatic and contains 1-3 heteroatoms. In polycyclic heteroaryl groups, at least one ring is an aromatic heterocycle. The heteroatoms are generally selected from N, O, and S. Specific examples of heteroaryl groups include, but are not limited to: furanyl, thiopheneyl, pyrroleyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoleyl, pyrazolyl, and pyrimidinyl.

[0239] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0240] The combinations of substituents and / or variables described in this disclosure are permitted only when these combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure is a compound that is sufficiently stable to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic agent.

[0241] In the embodiments of this disclosure, if there is a discrepancy between the compound name and the compound structure, the discrepancy can be determined by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structural formula shall prevail.

[0242] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0243] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0244] As used in this disclosure, the term "composition" means a product comprising specified amounts of each of the specified ingredients, and any product derived directly or indirectly from a combination of specified amounts of the specified ingredients. Those skilled in the art can vary the actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure so that the resulting amount of active compound is effectively targeted at a specific patient, composition, and route of administration to achieve the desired therapeutic response.

[0245] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering bioactive pharmaceutical agents to animals, particularly mammals.

[0246] The term "effective amount" refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof in sufficient quantity to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder.

[0247] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of reliable medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. The compounds disclosed herein can be reacted with their respective acids or bases to obtain their corresponding salts.

[0248] The term "stereoisomer" as used in this disclosure refers to isomers resulting from different spatial arrangements of atoms in a molecule. Stereoisomers include hindered rotation isomers, cis-trans isomers, enantiomers, diastereomers, tautomers, racemic mixtures thereof, and other mixtures, all of which fall within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a functional group isomer that has different hydrogen bonding sites through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. The term "diastereomer" refers to stereoisomers in which the molecule has two or more chiral centers and the molecules are not mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations in which the single bonds of double bonds or cyclic carbon atoms in a molecule cannot rotate freely. The term "hindered rotation isomer" refers to a stereoisomer that can be separated due to hindered or very slow rotation of single bonds.

[0249] In this disclosure, when a double bond is represented as When the double bond is cis-trans mixture, it indicates that the compound is a mixture of the cis and trans bonds of that double bond.

[0250] In this disclosure, unless otherwise specified, the component ratios of the eluent used in column chromatography or column chromatography are volume ratios. For example, "eluent: tetrahydrofuran / petroleum ether" indicates that the eluent is composed of a mixture of tetrahydrofuran and petroleum ether solvents. Those skilled in the art can determine a suitable solvent ratio through simple experimentation. In this invention, the reagent concentration unit M refers to mol / L; for example, 1 mM refers to 1 mmol / L.

[0251] In this disclosure, the compounds and related chiral intermediates can be prepared using methods for preparing similar structural compounds as described in WO2022103899A1 or WO2023220219A1. Those skilled in the art can adjust the starting materials and reaction conditions appropriately based on the structural characteristics of the target compound. The single stereoisomers of the compounds or related intermediates can also be resolved using the resolution conditions described in the aforementioned documents to obtain the corresponding single stereoisomers or sterically hindered isomers. Those skilled in the art can adjust the resolution conditions appropriately based on the structural characteristics of the target compound. Detailed Implementation

[0252] The present disclosure is further described in detail below through specific preparation examples and biological experiments. However, it should be understood that these examples and biological experiments are for illustrative purposes only and should not be construed as limiting the present disclosure in any way. Those skilled in the art will understand that, unless otherwise specified below, the materials used are well-known in the art and can be obtained commercially or by those skilled in the art based on published literature or conventional methods. Unless otherwise stated, all reactions in this disclosure are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, using a dry solvent. Wherein: (i) temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature, generally 15-35°C, preferably 20-30°C, more preferably 20-25°C; (ii) solvent removal is performed using a rotary evaporator under reduced pressure, with a bath temperature generally not exceeding 60°C; (iii) the reaction process is monitored by thin-layer chromatography (TLC); (iv) the final product has a satisfactory proton nuclear magnetic resonance spectrum (NMR). 1 H-NMR and / or mass spectrometry (MS) data.

[0253] Preparation Example 1: Synthesis of Intermediate IA

[0254] Step A:

[0255] 6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2.4 g, 11.3 mmol) and cyclopropylboronic acid (2.4 g, 28.3 mmol) were dissolved in ultradry 1,4-dioxane (20 mL) at room temperature. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (912 mg, 1.12 mmol) and potassium carbonate (3.2 g, 23.2 mmol) were added sequentially. The system was purged with nitrogen and then microwaved to 100 °C with stirring for 5 hours. After cooling to room temperature, the system was concentrated under reduced pressure to remove most of the dioxane. The crude product was then purified by silica gel column chromatography (100% petroleum ether-18% ethyl acetate / 72% petroleum ether) to obtain intermediate compound Int1 (820 mg). MS (ESI) M / Z: 177.2 [M+H] + .

[0256] Step B:

[0257] At room temperature, 2-bromo-4-aminopyridine (20 g, 115.60 mmol) was dissolved in acetonitrile (100 mL), and then N-iodosuccinimide (31.21 g, 138.72 mmol) was added and the mixture was heated to 90 °C and stirred for 48 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the acetonitrile, and then quenched with saturated sodium sulfite solution (100 mL). The mixture was extracted with dichloromethane (200 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (100% petroleum ether-25% ethyl acetate / 75% petroleum ether) to give compound IA-2 (12 g). MS (ESI) M / Z: 299.2 [M+H] + .

[0258] Step C:

[0259] IA-2 (11.6 g, 38.81 mmol) and ethyl acrylate (3.89 g, 38.81 mmol) were dissolved in ultradry N,N-dimethylformamide (150 mL) at room temperature. Then, palladium acetate (0.43 g, 1.90 mmol), triethylamine (5.89 g, 58.22 mmol), and tri-o-tolylphosphine (1.18 g, 3.88 mmol) were added sequentially. After nitrogen purging, the mixture was heated to 100 °C and stirred for 3 hours. The mixture was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed successively with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (100% petroleum ether-50% ethyl acetate / 50% petroleum ether) to obtain compound IA-3 (7.8 g). MS (ESI) M / Z: 273.0 [M+H] + .

[0260] Step D:

[0261] IA-3 (7 g, 25.82 mmol) was dissolved in ethanol (100 mL) at room temperature, followed by the addition of sodium ethoxide / ethanol solution (22 mL, 20% concentration). The system was heated to 60 °C and stirred for 3 hours. After cooling to room temperature, the solution was added dropwise to dilute hydrochloric acid (1 M), filtered, and the filter cake was washed with water (10 mL × 3). After drying, compound IA-4 (5 g) was obtained. MS (ESI) M / Z: 225.0 [M + H] + .

[0262] Step E:

[0263] IA-4 (950 mg, 4.26 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL) at room temperature, followed by the sequential addition of zinc cyanide (988 mg, 8.44 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (684 mg, 0.84 mmol), and zinc powder (55 mg, 0.84 mmol). The system was purged with nitrogen and then heated to 120 °C in an oil bath for 2 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane / isopropanol. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was directly purified by reverse-phase chromatography (Regular C18 20-40 μm, 80 g, 0-30%, pure water / methanol) to obtain compound IA-5 (534 mg). MS (ESI) M / Z: 172.1 [M+H] + .

[0264] Step F:

[0265] Phosphorus oxychloride (6 mL) was added to IA-5 (534 mg, 3.12 mmol) at room temperature. The system was then purged with nitrogen and heated in an oil bath to 80 °C for 2 hours. Phosphorus oxychloride was removed by concentration under reduced pressure. Ethyl acetate (10 mL) was added and the mixture was sonicated to dissolve the phosphorus oxychloride. The pH was then adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound IA-6 (477 mg). MS (ESI) M / Z: 190.1 [M+H] + .

[0266] Step G:

[0267] Compound IA-6 (50 mg, 0.26 mmol) and 6-cyclopropyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (61 mg, 0.34 mmol) were dissolved in ultradry 1,4-dioxane (2 mL) at room temperature. Then, tris(dibenzylacetone)dipalladium (24 mg, 0.026 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (15 mg, 0.026 mmol), and cesium carbonate (254 mg, 0.78 mmol) were added sequentially. After nitrogen purging, the mixture was heated to 100 °C in an oil bath for 3 hours. The dioxane was removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to give compound IA-7 (30 mg). MS (ESI) M / Z: 330.2 [M+H] + .

[0268] Step H:

[0269] Compound IA-7 (30 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL) at room temperature. After purging with nitrogen, the system was cooled to -78 °C using dry ice / ethyl acetate. Then, diisobutylaluminum hydride (0.23 mL, 2.5 eq) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 2 hours. The reaction was quenched by adding water (3 mL) at -20 °C. Insoluble matter was removed by diatomaceous earth filtration. The mother liquor was allowed to stand and separate into layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound IA (30 mg). MS (ESI) M / Z: 334.2 [M+H] + .

[0270] Preparation Example 2: Synthesis of Intermediate IB

[0271] Step A: At 0°C, 23 g (147.34 mmol) of 3-fluoro-4-hydroxybenzoic acid was slowly added to chlorosulfonic acid (147 mL, 2.21 mol). The reaction mixture was then stirred at 80°C for 4 hours. The reaction solution was slowly added dropwise to ice water (220 mL), filtered, and the filter cake was washed with water (40 mL × 2 times). The filter cake was collected and concentrated under reduced pressure to obtain IB-2 (28.1 g). The crude product was used directly in the next step.

[0272] Step B: Compound IB-2 (25 g, 98.43 mmol) was dissolved in toluene (492 mL) at 0 °C. Triphenylphosphine (90.36 g, 344.51 mmol) was then added to the solution. The reaction mixture was stirred at 90 °C for 4 hours. The reaction mixture was quenched with saturated sodium bicarbonate (180 mL), and the mixture was extracted with ethyl acetate (50 mL × 2 times). The aqueous phase was adjusted to pH 3 with 2 M dilute hydrochloric acid at 0 °C and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined and washed with saturated brine (80 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give IB-3 (14.3 g). MS (ESI) M / Z: 189.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),11.59(s,1H),7.83(dd,J=1.6,0.8Hz,1H),7.60(dd,J=10.8,2.0Hz,1H).

[0273] Step C: Under nitrogen protection at room temperature, compound IB-3 (13.1 g, 69.84 mmol) was dissolved in methanol (175 mL). Then, concentrated sulfuric acid (20.53 g, 209.52 mmol) was slowly added dropwise to the solution. The reaction mixture was then stirred at 80 °C for 4 hours. The reaction solution was concentrated under reduced pressure and diluted with ice water (70 mL). The mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give IB-4 (8.6 g). MS (ESI) M / Z: 203.1 [M+H] + .

[0274] Step D: Compound IB-4 (8.2 g, 40.57 mmol) was dissolved in N,N-dimethylformamide (203 mL) at room temperature. Then, 1,3-dibromopropane (8.2 g, 40.57 mmol) and cesium carbonate (66.1 g, 202.85 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give IB-5 (5.9 g). MS (ESI) M / Z: 243.2 [M+H] + .

[0275] Step E: Compound IB-5 (5.31 g, 21.93 mmol) was dissolved in methanol (109 mL) and water (55 mL) at 0 °C. Then, potassium persulfate complex salt (70693-62-8, 7.42 g, 12.06 mmol) was added to the above solution. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (80 mL × 3 times). The combined organic phases were washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give IB-6 (4.8 g). MS (ESI) M / Z: 259.2 [M+H] + .

[0276] Step F: Under nitrogen protection at 0°C, compound IB-6 (2.35 g, 9.10 mmol) was dissolved in chloroform (23 mL). Diethylaminosulfur trifluoride (29.3 g, 182.0 mmol) was then added dropwise to the solution. The reaction mixture was stirred at 50°C for 48 hours. The reaction mixture was quenched by slowly pouring it into ice-cold saturated sodium bicarbonate (60 mL). The mixture was extracted with dichloromethane (40 mL × 3 times), and the combined organic phases were washed with saturated brine (50 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give IB-7 (525 mg). MS (ESI) M / Z: 261.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.93 (t, J=1.6Hz, 1H), 7.75 (dd, J=9.8, 2.2Hz, 1H), 5.98-5.93 (m, 0.5H) ,5.86-5.82(m,0.5H),4.64-4.56(m,1H),4.17-4.08(m,1H),3.91(s,3H),2.66-2.56(m,2H). 19 F NMR(376MHz, CDCl3)δ-129.20(s,1F),-153.74(s,1F).

[0277] Step G: Compound IB-7 (1.21 g, 4.65 mmol) was dissolved in tetrahydrofuran (8 mL) / methanol (4 mL) and water (4 mL) at 0 °C. Then, sodium hydroxide solid (372 mg, 9.30 mmol) was added to the solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was cooled to 0 °C, diluted with water (10 mL), and then adjusted to pH 4 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude IB-8 (1.04 g). MS (ESI) M / Z: 247.2 [M+H] + .

[0278] Step H: Compound IB-8 (1.4 g, 5.69 mmol) was dissolved in methanol (26 mL) and water (13 mL) at 0 °C. Subsequently, potassium persulfate complex salt (CAS No.: 70693-62-8, 10.49 g, 17.07 mmol) was added to the above solution. The reaction mixture was then stirred at room temperature for 16 hours. The reaction solution was diluted with water (25 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 5% sodium bisulfite (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 300 mg of the crude product was resolved by a chiral column (Daicel AD-3 (4.6*100 mm, 3.0 μm), mobile phase: carbon dioxide-methanol [0.2% ammonia-methanol solution (7 M)] = 85 / 15) to obtain 100 mg of compound (IB, retention time: 1.481 min, target analyte) and 95 mg of compound (IB-A, retention time: 1.723 min). IB: MS (ESI) M / Z: 279.1 [M+H] + .ee% = 100%. 1H NMR(400MHz, DMSO-d6)13.88(s,1H),8.23-8.19(m,1H),8.17(dd,J=10.0,2.0Hz,1H),6.35(dd,J=5.4,1.8Hz,1H),6. 24(dd,J=5.6,1.6Hz,1H),4.62(dt,J=12.8,3.8Hz,1H),4.17(t,J=11.6Hz,1H),2.91-2.70(m,1H),2.66-2.55(m,1H). 19 F NMR(300MHz,DMSO-d6)δ-127.00,-187.12ppm.

[0279] Preparation Example 3: Synthesis of Intermediate IC

[0280] Step A: IA-6 (56 mg, 0.30 mmol) was dissolved in ultra-dry dichloromethane (3 mL) at room temperature. The system was then purged with nitrogen and cooled to -78°C using a dry ice / ethyl acetate bath. Diisobutylaluminum hydride (0.88 mL, 2.5 eq) was slowly added dropwise, and the reaction proceeded for 3 hours. The system was then heated to 0°C, quenched with water (10 mL) in an ice bath, and filtered through diatomaceous earth to remove insoluble aluminum salts. Dichloromethane (10 mL × 2) was added to the mother liquor for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude IC-1 (56 mg), which was directly used in the next reaction. MS (ESI) M / Z: 194.1 [M+H] + .

[0281] Step B: Dissolve IC-1 (56 mg, 0.17 mmol, purity: 60%) in dichloromethane (3 mL) at room temperature, then add N,N-diisopropylethylamine (0.066 g, 0.51 mmol) and di-tert-butyl dicarbonate (0.056 g, 0.26 mmol) sequentially and stir for half an hour. Quench the mixture with water (10 mL), then extract with dichloromethane (10 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is then purified by plate chromatography (dichloromethane / methanol = 10:1) to obtain IC (26 mg). MS (ESI) M / Z: 294.1 [M+H] + .

[0282] Preparation Example 4: Synthesis of Intermediate ID

[0283] Step A: Compound ID-1 (10 g, 57.47 mmol) was dissolved in tetrahydrofuran (249 mL) at room temperature. The reaction mixture was then cooled to 0 °C, and potassium carbonate (15 g, 114.94 mmol) and iodine (32 g, 129.4 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was quenched with ice-cold 10% sodium thiosulfate solution (300 mL). The mixture was extracted with ethyl acetate (150 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ID-2 (15 g). MS (ESI) M / Z: 300.0 [M+H] + .

[0284] Step B: At room temperature, compound ID-2 (9.0 g, 30 mmol) was dissolved in N,N-dimethylformamide (75 mL). The reaction mixture was then cooled to 0 °C, and potassium carbonate (5.1 g, 33 mmol) and iodoethane (8.3 g, 60 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with ice water (300 mL). The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (150 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ID-3 (8.5 g). MS (ESI) M / Z: 328.0 [M+H] + .

[0285] Step C: Under nitrogen protection at room temperature, compound ID-3 (8.5 g, 26 mmol) was dissolved in 1,4-dioxane (130 mL) and water (14 mL). Subsequently, potassium vinyltrifluoroborate (6.6 g, 49.4 mmol), palladium acetate (583 mg, 2.6 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (1 g, 2.6 mmol), and potassium carbonate (7.2 g, 52 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 80 °C for 4 hours. The reaction mixture was quenched with ice water (200 mL). The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ID-4 (1.35 g). MS(ESI)M / Z:228.2[M+H] + .

[0286] Step D: Under nitrogen protection at room temperature, compound ID-4 (1.35 mg, 5.9 mmol) was dissolved in tetrahydrofuran (8.5 mL). The reaction mixture was then cooled to 0 °C, and sodium iodide (177 mg, 1.2 mmol) and (trifluoromethyl)trimethylsilane (3.3 g, 23.6 mmol) were added sequentially. The reaction mixture was then stirred at 70 °C for 2 hours. The reaction mixture was quenched with ice water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the combined organic phases were washed with saturated brine (50 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ID-5 (1.3 g). MS (ESI) M / Z: 278.2 [M+H] + .

[0287] Step E: Under nitrogen protection at room temperature, compound ID-5 (200 mg, 0.72 mmol) was dissolved in 1,4-dioxane (3.6 mL). Subsequently, hexamethyldistin (260 mg, 0.79 mmol) and bis(triphenylphosphine)palladium dichloride (50 mg, 0.07 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 100 °C for 1 hour. The reaction mixture was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ID-6 (200 mg). MS (ESI) M / Z: 364.3 [M+H] + .

[0288] Step F: Under nitrogen protection at room temperature, compound ID-6 (200 mg, 0.55 mmol) was dissolved in 1,4-dioxane (2 mL). Subsequently, IC (60 mg, 0.20 mmol) and bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 100 °C for 2 hours. The reaction mixture was quenched with ice water (20 mL). The mixture was extracted with dichloromethane (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ID-7 (76 mg). MS (ESI) M / Z: 457.7 [M+H] + .

[0289] Step G: Compound ID-7 (60 mg, 0.13 mmol) was dissolved in an aqueous hydrochloric acid solution (2.4 mL, 6 M) at room temperature. The reaction mixture was then stirred at room temperature for 0.5 hours. The reaction solution was directly lyophilized to obtain compound ID (70 mg). MS (ESI) M / Z: 357.3 [M+H] + .

[0290] Preparation Example 5: Synthesis of Intermediate IE

[0291] Step A: At room temperature, compound IE-1 (200 mg, 0.74 mmol) and 1,1,1,2,2,2-hexabutyldistannane (0.52 g, 0.89 mmol) were dissolved in ultra-dry 1,4-dioxane (5 mL), followed by the addition of tetra(triphenylphosphine)palladium (0.17 g, 0.15 mmol). After nitrogen purging, the system was heated to 120°C and stirred for 8 hours. After cooling, water (10 mL) and ethyl acetate (20 mL × 2) were added directly to the system. The extracted organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound IE-2 (420 mg). The crude product was used directly in the next step. MS (ESI) M / Z: 481.3 [M+H] + .

[0292] Step B: Compound IC (100 mg, 0.34 mmol) and compound IE-2 (0.33 g, 0.68 mmol) were dissolved in ultradry 1,4-dioxane (3 mL) at room temperature. Then, bis(triphenylphosphine)palladium(II) chloride (0.048 g, 0.068 mmol) was added. The system was then purged with nitrogen and heated to 110°C with stirring for 5 hours. Potassium fluoride aqueous solution (20 mL) was added directly to the system, and extraction was performed with ethyl acetate (10 mL × 2). The organic phase was washed again successively with potassium fluoride aqueous solution (20 mL × 2) and saturated brine (10 mL × 2). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated. The crude product was purified by column chromatography (100% petroleum ether-12% ethyl acetate / petroleum ether) to obtain compound IE-3 (98 mg). MS (ESI) M / Z: 450.3 [M+H] + .

[0293] Step C: Compound IE-3 (98 mg, 0.22 mmol) was added to a hydrochloric acid / dioxane solution (2 M, 20 mL), and the reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude compound IE (103 mg), which was used directly in the next step. MS (ESI) M / Z: 350.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.57(s,1H),8.89(d,J=8.53Hz,1H),8.59(d,J=8.53Hz,1H),8.29(s,1H),8.18(dd,J =9.04,7.53Hz,1H),8.01(d,J=7.28Hz,1H),7.64-7.60(m,1H),4.56(s,2H),4.27(br d,J=12.30Hz,2H),3.93-3.81(m,2H),3.00(t,J=11.80Hz,2H),1.35(d,J=6.27Hz,6H).

[0294] Preparation Example 6: Synthesis of Intermediate IF

[0295] Step A: The mixture of compound IF-1 (1 g, 3.92 mmol), cis-2,6-dimethylmorpholine (451.87 mg, 3.92 mmol), cuprous iodide (224.16 mg, 1.18 mmol), anhydrous potassium phosphate (2.50 g, 11.77 mmol), and anhydrous toluene (20 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 95 °C under nitrogen for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–5% ethyl acetate / n-hexane eluent gradient) to obtain compound IF-2 (255 mg). MS (ESI) M / Z: 289.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 6.57(dd,J=7.39,1.55Hz,1H),6.18(dd,J=11.56,1.67Hz,1H),4.03-3.94(m,2H),3 .68(ddd,J=10.55,6.32,2.56Hz,2H),2.60-2.51(m,2H),1.28(s,3H),1.26(s,3H).

[0296] Step B: The mixture of IF-2 (255 mg, 881.92 μmol), hexamethyldistin (227.85 μL, 1.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (64.53 mg, 88.19 μmol) in anhydrous toluene (6 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 110 °C under nitrogen for 2 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure to obtain compound IF-3 (600 mg). This was used directly in the next reaction. MS (ESI) M / Z: 375.1 [M+H] + .

[0297] Step C: The mixture of compound IF-3 (0.6 g, 1.61 mmol), compound IC (260 mg, 885.11 μmol), and palladium dichloride bis(triphenylphosphine) (62.13 mg, 88.51 μmol) in dioxane (6 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 100 °C under nitrogen for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–40% ethyl acetate / n-hexane eluent gradient) to obtain compound IF-4 (330 mg). This was used directly in the next reaction. MS (ESI) M / Z: 468.4 [M+H] + .

[0298] Step D: Add 0.1 mL of trifluoroacetic acid dropwise to a solution of compound IF-4 (30 mg, 64.17 μmol) in 1 mL of dichloromethane. Stir the mixture at 20°C for 1 hour. Dilute the reaction solution with 3 mL of water and 2 mL of dichloromethane to separate the aqueous phase. Then, alkalize the aqueous phase to pH 9 with a saturated sodium bicarbonate solution, and then extract twice with 4 mL of dichloromethane to separate the organic phase. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound IF (25 mg), which can be used directly in the next reaction. MS (ESI) M / Z: 368.3 [M+H] + .

[0299] Example 1: Preparation of Compound 1

[0300] Synthesis steps:

[0301] Step A: Methyl 4-amino-3-nitrobenzene (20 g, 101.99 mmol) was dissolved in dichloromethane (510 mL) at 0 °C. Liquid bromine (21.19 g, 132.59 mmol) was then slowly added dropwise to the solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was quenched by slowly adding dropwise to ice water (220 mL) and 10% sodium thiosulfate (100 mL). The mixture was extracted with dichloromethane (100 mL × 3 times), and the combined organic phases were washed with saturated brine (100 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compounds 1-2 (19.5 g). MS (ESI) M / Z: 275.1 [M+H] + .

[0302] Step B: Compounds 1-2 (14.5 g, 52.90 mmol) were dissolved in ethanol (176 mL) and water (88 mL) at 0 °C. Iron powder (14.81 g, 264.50 mmol) and ammonium chloride (28.31 g, 529.00 mmol) were added sequentially to the above solution. The reaction system was stirred at 80 °C for 2 hours. The reaction solution was filtered, and the filter cake was washed with water (50 mL × 2 times). The filtrate was collected and concentrated under reduced pressure. Saturated sodium bicarbonate (180 mL) was added dropwise to the concentrate to adjust the pH to 8, and then extracted with ethyl acetate (90 mL × 3 times). The organic phases were combined and washed with saturated brine (80 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 1-3 (10.75 g). MS (ESI) M / Z: 245.1 [M+H] + .

[0303] Step C: Under nitrogen protection at room temperature, compounds 1-3 (1.2 g, 4.92 mmol) were dissolved in formic acid (9.4 mL). The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was quenched with water (40 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compounds 1-4 (810 mg). MS (ESI) M / Z: 255.1 [M+H] + .

[0304] Step D: Under nitrogen protection at room temperature, compounds 1-4 (480 mg, 1.89 mmol) were dissolved in 1,4-dioxane (9.5 mL). (4-methoxyphenyl)methanethiol (350 mg, 2.27 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (110 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (174 mg, 0.19 mmol), and N,N-diisopropylethylamine (976 mg, 7.56 mmol) were added sequentially to the above solution. The reaction mixture was stirred at 120 °C for 4 hours. The reaction solution was quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compounds 1-5 (270 mg). MS (ESI) M / Z: 329.2 [M+H] + .

[0305] Step E: Compounds 1-5 (240 mg, 21.93 mmol) were dissolved in trifluoroacetic acid (3.6 mL) at 0 °C. The reaction mixture was then stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure to give 156 mg of compounds 1-6. MS (ESI) M / Z: 209.2 [M+H] + .

[0306] Step F: Compounds 1-6 (156 mg, 0.75 mmol) were dissolved in N,N-dimethylformamide (3.8 mL) at 0 °C. 1,3-dibromopropane (228 mg, 1.13 mmol) and potassium carbonate (414 mg, 3.00 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compounds 1-7 (130 mg). MS (ESI) M / Z: 249.2 [M+H] + .

[0307] Step G: Compounds 1-7 (110 mg, 0.44 mmol) were dissolved in methanol (2.2 mL) and water (1.1 mL) at 0 °C. Potassium persulfate (811 mg, 1.32 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 3 hours. The reaction solution was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (15 mL × 3 times). The organic phases were combined and washed with 5% sodium bisulfite (10 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 1-8 (115 mg).

[0308] Step H: Compounds 1-8 (115 mg, 0.41 mmol) were dissolved in tetrahydrofuran (2.2 mL), methanol (1.1 mL), and water (1.1 mL) at 0 °C. Sodium hydroxide (33 mg, 0.82 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with water (5 mL), then cooled to 0 °C, and adjusted to pH 3 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined. The extract was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 1-9 (105 mg). MS (ESI) M / Z: 267.2 [M+H] + .

[0309] Step I: IA (30 mg) and 1-9 (24 mg, 0.09 mmol) were dissolved in ultradry tetrahydrofuran (2 mL) at room temperature. Then, N,N-diisopropylethylamine (45 μL) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (40 mg, 0.13 mmol) were added sequentially, and the mixture was reacted at room temperature for 16 hours. The mixture was filtered and purified by reverse-phase chromatography (Regular C18 20-40 μm, 80 g, 0-45%, 0.1% formic acid / pure water-acetonitrile), followed by lyophilization to obtain compound 1 (4.1 mg). MS (ESI) M / Z: 582.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.00 (s, 1H), 8.61 (d, J = 1.4Hz, 1H), 8.44 (d, J = 1.4Hz, 1H), 8.38 (d, J=9.2Hz,1H),8.10–7.97(m,2H),7.87(s,1H),7.69(s,1H),7.12(d,J=8.1Hz,1H),6.85( d,J=8.1Hz,1H),4.93(d,J=5.0Hz,2H),4.85–4.72(m,2H),4.45(dd,J=5.3,3.7Hz,2H),4 .34(dd,J=5.3,3.7Hz,2H),3.72(t,J=7.0Hz,2H),2.65–2.52(m,2H),0.97–0.84(m,4H).

[0310] Example 2 Preparation of Compound 2

[0311] Step A: At 0°C, compound IA-6 (210 mg, 1.11 mmol) was dissolved in diethyl ether (7.4 mL). Tetraisopropyl titanate (631 mg, 2.22 mmol) was then added dropwise to the solution, and the mixture was stirred for 7 minutes. Next, a 3.4 M solution of ethyl magnesium bromide in tetrahydrofuran (0.6 mL, 2.00 mmol) was added dropwise, the mixture was brought to room temperature, and stirred for 1 hour. The mixture was then cooled to 0°C, and boron trifluoride diethyl ether (237 mg, 1.67 mmol) was added dropwise. The mixture was then brought to room temperature again, and stirring continued for 16 hours. The reaction mixture was quenched with water (20 mL), and the pH was adjusted to 2 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 2). The resulting aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-1 (65 mg). MS (ESI) M / Z: 220.2 [M+H] + .

[0312] Step B: Compound 2-1 (65 mg, 0.29 mmol) was dissolved in dichloromethane (2.9 mL) at 0 °C. Then, di-tert-butyl dicarbonate (101 mg, 0.46 mmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 16 hours. The reaction solution was quenched with water (20 mL). The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-2 (60 mg). MS (ESI) M / Z: 320.3 [M + H] + .

[0313] Step C: Under nitrogen protection at room temperature, compound Int1 (37 mg, 0.21 mmol), compound 2-2 (60 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (35 mg, 0.038 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (22 mg, 0.038 mmol), and cesium carbonate (124 mg, 0.38 mmol) were dissolved in 1,4-dioxane (1.9 mL). The reaction mixture was then stirred at 100 °C for 3 hours. The reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-3 (55 mg). MS(ESI)M / Z:460.3[M+H] + .

[0314] Step D: Compound 2-3 (45 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL) at 0 °C. Then, 4 M 1,4-dioxane hydrochloride (0.5 mL) was added dropwise to the solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 2-4 hydrochloride (35 mg). MS (ESI) M / Z: 360.3 [M+H] + .

[0315] Step E: Compound IB (28 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL) at 0 °C. Then, 1-hydroxybenzotriazole (18 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol), N,N-diisopropylethylamine (39 mg, 0.30 mmol), and hydrochloride salts of compounds 2-4 (35 mg, 0.10 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (15 mL). The mixture was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give compound 2 (17.81 mg). MS(ESI)M / Z:620.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 9.03 (s, 1H), 8.40-8.32 (m, 2H), 8.25 (d, J = 9.2Hz, 1H), 8.15 (d, J = 9. 2Hz,1H),7.47(s,1H),7.19(d,J=8.0Hz,1H),6.96(d,J=8.4Hz,1H),6.37-6.31(m,0.5H),6.26-6.20(m,0. 5H),4.62(dt,J=13.2,3.6Hz,1H),4.33-4.22(m,4H),4.18(t,J=11.8Hz,1H),2.93-2.72(m,1H),2.66-2. 56(m,1H),2.05-1.96(m,1H),1.75-1.64(m,2H),1.40-1.31(m,2H),0.90-0.82(m,2H),0.81-0.75(m,2H).

[0316] Example 3 Preparation of Compound 3

[0317] Step A: Under nitrogen protection in an ice-water bath, 15 g (62.2 mmol) of compound 4-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one was dissolved in 125 mL of methanol. Then, sodium borohydride (2.37 g, 62.2 mmol) was slowly added to the solution. The reaction mixture was then stirred for 2 hours. The reaction solution was quenched in ice water (80 mL). The mixture was concentrated under reduced pressure, and the concentrate was extracted with dichloromethane (40 mL × 3). The organic phases were combined and washed with saturated brine (40 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3-2 (13.3 g). MS (ESI) M / Z: 225.0 [M-OH] - .

[0318] Step B: Compound 3-2 (13.3 g, 55.0 mmol) was dissolved in dichloromethane (270 mL) under nitrogen protection in an ice-water bath. Triethylsilane (31.9 g, 274.8 mmol) and boron trifluoride diethyl ether (15.6 g, 110.0 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction solution was quenched in ice water (100 mL). The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-3 (11.6 g). 1 H NMR (400MHz, DMSO-d6) δ7.28(d,J=8.8Hz,1H),6.73(d,J=8.4Hz,1H),3.76(s,3H),2.94-2.78(m,4H),2.10-1.94(m,2H).

[0319] Step C: Under nitrogen protection at room temperature, compound 3-3 (11.6 g, 51.3 mmol), oxalic acid (6.93 g, 77.0 mmol), palladium acetate (924 mg, 4.11 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.49 g, 2.57 mmol), N,N-diisopropylethylamine (9.9 g, 77.0 mmol), and acetic anhydride (7.85 g, 77.0 mmol) were dissolved in N,N-dimethylformamide (171 mL). The reaction mixture was then stirred at 100 °C for 48 hours. The reaction solution was quenched in ice water (350 mL). The mixture was adjusted to pH 2 with 3M dilute hydrochloric acid, extracted with ethyl acetate (180 mL × 3), and the organic phases were combined and washed with saturated brine (200 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compounds 3-4 (4 g). MS (ESI) M / Z: 193.2 [M+H] + .

[0320] Step D: Under nitrogen protection in an ice-water bath, compound 3-4 (4.5 g, 23.3 mmol) was dissolved in dichloromethane (58.5 mL), followed by the addition of boron tribromide (4.5 mL). The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was quenched in ice water (200 mL). The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined and washed with saturated brine (200 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-5 (1.5 g). MS (ESI) M / Z: 179.2 [M+H] + .

[0321] Step E: Under nitrogen protection in an ice-water bath, compound 3-5 (1.3 g, 7.4 mmol) was slowly added to chlorosulfonic acid (7.4 mL). The reaction mixture was then heated to 80 °C and stirred for 4 hours. The reaction solution was quenched by slowly adding it dropwise to ice water (100 mL), filtered, and the filter cake was washed with water (20 mL × 3 times). The solid was collected, dried under vacuum, and 3-6 (1.3 g) was obtained. MS (ESI) M / Z: 277.1 [M+H] + .

[0322] Step F: Compound 3-6 (1.3 g, 4.7 mmol) was dissolved in toluene (23.5 mL) under nitrogen protection in an ice-water bath. Triphenylphosphine (4.3 g, 16.45 mmol) was then added to the solution. The reaction mixture was then heated to 90 °C and stirred for 4 hours. The reaction mixture was quenched dropwise in an ice-cold saturated sodium bicarbonate aqueous solution (50 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium bicarbonate (50 mL), and all aqueous phases were combined. The aqueous phases were adjusted to pH 3 with 3 M dilute hydrochloric acid, extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3-7 (630 mg). MS (ESI) M / Z: 211.2 [M+H] + .

[0323] Step G: Under nitrogen protection in an ice-water bath, compound 3-7 (630 mg, 3.0 mmol) was dissolved in methanol (7.5 mL), followed by the dropwise addition of concentrated sulfuric acid (0.6 mL). The reaction system was then heated to 80 °C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was quenched in ice water (50 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give compound 3-8 (350 mg). MS (ESI) M / Z: 225.0 [M+H] + .

[0324] Step H: Compound 3-8 (325 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (14.5 mL) under nitrogen protection in an ice-water bath. Then, 1,3-dibromopropane (292 mg, 1.45 mmol) and cesium carbonate (2.4 g, 7.25 mmol) were added sequentially to the solution. The reaction mixture was then heated to room temperature and stirred for 4 hours. The reaction solution was quenched in ice water (100 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-9 (198 mg). MS (ESI) M / Z: 265.2 [M+H] + .

[0325] Step I: Compound 3-9 (178 mg, 0.67 mmol) was dissolved in a mixture of methanol (3.4 mL) and water (1.4 mL) under nitrogen protection in an ice-water bath. Subsequently, potassium persulfate complex salt (70693-62-8, 1.2 g, 2.02 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 3 hours. The reaction solution was quenched in ice water (50 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-10 (223 mg). MS (ESI) M / Z: 297.0 [M+H] + .

[0326] Step J: Compound 3-10 (200 mg, 0.68 mmol) was dissolved in a mixed solution of tetrahydrofuran (1.7 mL), methanol (0.85 mL), and water (0.85 mL) under nitrogen protection in an ice-water bath. Sodium hydroxide (54 mg, 1.36 mmol) was then added to the solution. The reaction mixture was then heated to room temperature and stirred for 2 hours. The reaction solution was quenched in ice water (50 mL) and adjusted to pH 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-11 (200 mg). MS (ESI) M / Z: 283.0 [M+H] + .

[0327] Step K: Compound 3-11 (15 mg, 0.054 mmol) was dissolved in dichloromethane (0.6 mL) under nitrogen protection in an ice-water bath. Subsequently, 1-hydroxybenzotriazole (8.5 mg, 0.063 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg, 0.063 mmol), N,N-diisopropylethylamine (17.4 mg, 0.135 mmol), and IA (15 mg, 0.045 mmol) were added sequentially to the above solution. The reaction mixture was then heated to room temperature and stirred for 2 hours. The reaction solution was quenched in ice water (20 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the combined organic phases were washed with saturated brine (50 mL). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (0.1% ammonium bicarbonate aqueous solution / acetonitrile), and lyophilized to give compound 3 (9.1 mg). MS (ESI) M / Z: 598.2 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ9.17(t,J=4.8Hz,1H),9.10(s,1H),8.30(d,J=9.2Hz,1H),8 .19(d,J=8.8Hz,1H),8.03(s,1H),7.50(s,1H),7.21(d,J=8.0Hz,1H),6.98(d,J=8.0 Hz,1H),4.68(d,J=4.8Hz,2H),4.37-4.18(m,6H),3.59-3.50(m,2H),3.20(t,J=7.0 Hz,2H),2.90(t,J=7.2Hz,2H),2.27(brs,2H),2.13-1.94(m,3H),0.94-0.70(m,4H).

[0328] Example 4: Preparation of Compound 4

[0329] Step A: Under nitrogen protection at room temperature, compound 4-1 (500 mg, 1.97 mmol) was dissolved in 1,4-dioxane (9.9 mL). Then, (4-methoxyphenyl)methanethiol (364 mg, 2.36 mmol), tris(dibenzylacetone)dipalladium (180 mg, 0.2 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (114 mg, 0.2 mmol), and N,N-diisopropylethylamine (1.02 g, 7.88 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 120 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and washed with saturated brine (30 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4-2 (700 mg). MS (ESI) M / Z: 329.2 [M+H] + .

[0330] Step B: Under nitrogen protection at room temperature, compound 4-2 (300 mg, 0.92 mmol) was dissolved in trifluoroacetic acid (4.6 mL). The reaction mixture was then stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure, quenched with water (20 mL), and adjusted to pH 8 by dropwise addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-3 (330 mg). MS (ESI) M / Z: 209.1 [M+H] + .

[0331] Step C: Compound 4-3 (330 mg, 1.59 mmol) was dissolved in N,N-dimethylacetamide (8 mL) at room temperature. Then, 1,3-dibromopropane (481 mg, 2.38 mmol) and cesium carbonate (1.14 g, 3.5 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was quenched with ice water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4-4 (160 mg). MS (ESI) M / Z: 249.0 [M+H] + .

[0332] Step D: Under nitrogen protection at room temperature, compound 4-4 (160 mg, 0.65 mmol) was dissolved in methanol (3.2 mL) and water (1.6 mL). The solution was then cooled to 0 °C, and potassium persulfate complex salt (70693-62-8, 1.2 g, 1.94 mmol) was added in portions. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4-5 (140 mg). MS (ESI) M / Z: 281.0 [M+H] + .

[0333] Step E: Compounds 4-5 (140 mg, 0.50 mmol) were dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL) at room temperature. Sodium hydroxide (40 mg, 1.0 mmol) was then added to the solution. The reaction mixture was stirred for 2 hours. The reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 3 with 2 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 4-6 (80 mg). MS (ESI) M / Z: 267.0 [M+H] + .

[0334] Step F: Under nitrogen protection at room temperature, compounds 4-6 (37 mg, 0.14 mmol) were dissolved in dichloromethane (2.1 mL). The solution was then cooled to 0 °C, and 1-hydroxybenzotriazole (20 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol), N,N-diisopropylethylamine (41 mg, 0.32 mmol), and IA (35 mg, 0.11 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was quenched with ice water (20 mL). The mixture was extracted with dichloromethane (100 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give compound 4 (20 mg). MS(ESI)M / Z:582.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.58(t,J=5.8Hz,1H),9.11(s,1H),8.81(d,J=1.2Hz,1H),8.56(d ,J=1.6Hz,1H),8.50(s,1H),8.30(d,J=9.2Hz,1H),8.20(d,J=9.2Hz,1H),7.50(s,1H),7. 20(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),4.79-4.71(m,4H),4.34-4.22(m,4H),3.99(t, J=6.2Hz,2H),2.60-2.53(m,2H),2.05-1.97(m,1H),0.90-0.83(m,2H),0.82-0.75(m,2H).

[0335] Example 5: Preparation of Compound 5

[0336] Step A: Methyl 7-bromo-1H-indazole-5-carboxylate (3.0 g, 11.81 mmol) was dissolved in acetonitrile (50 mL) and acetic acid (10 mL) at 0 °C. A selective fluorine reagent (10.46 g, 29.53 mmol) was then added to the solution. The reaction mixture was then stirred at 120 °C for 40 hours. The reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5-1 (1.32 g). MS (ESI) M / Z: 273.0 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ13.51 (s, 1H), 8.37 (s, 1H), 8.14 (d, J = 1.2Hz, 1H), 3.89 (s, 3H). 19 F NMR(300MHz,DMSO-d6)δ-131.21(s,1F).

[0337] Step B: Under nitrogen protection at 0°C, compound 5-1 (455 mg, 1.67 mmol) was dissolved in 1,4-dioxane (8.4 mL). Then, (4-methoxyphenyl)methanethiol (308 mg, 2.00 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (97 mg, 0.17 mmol), tris(dibenzylacetone)dipalladium (153 mg, 0.17 mmol), and N,N-diisopropylethylamine (862 mg, 6.68 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 120°C for 3 hours. The reaction mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5-2 (410 mg). MS (ESI) M / Z: 347.2 [M+H] + .

[0338] Step C: Under nitrogen protection at room temperature, compound 5-2 (375 mg, 1.08 mmol) was dissolved in trifluoroacetic acid (5.4 mL). The reaction mixture was then stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water (15 mL), and adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 5-3 (245 mg). MS (ESI) M / Z: 227.2 [M+H] + .

[0339] Step D: Compound 5-3 (245 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5.4 mL) at 0 °C. Then, 1,3-dibromopropane (327 mg, 1.62 mmol) and potassium carbonate (597 mg, 4.32 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 4 hours. The reaction solution was quenched with water (45 mL). The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5-4 (106 mg). MS (ESI) M / Z: 267.2 [M+H] + .

[0340] Step E: Compound 5-4 (60 mg, 0.23 mmol) was dissolved in methanol (1.1 mL) and water (0.55 mL) at 0 °C. Subsequently, potassium persulfate complex salt (70693-62-8, 424 mg, 0.69 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 5 hours. The reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 5-5 (65 mg). MS (ESI) M / Z: 299.2 [M+H] + .

[0341] Step F: Compound 5-5 (62 mg, 0.21 mmol) was dissolved in tetrahydrofuran (0.4 mL) / methanol (0.2 mL) and water (0.2 mL) at 0 °C. Subsequently, sodium hydroxide solid (17 mg, 0.42 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL) and then adjusted to pH 4 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 5-6 (55 mg). MS (ESI) M / Z: 283.1 [MH] - .

[0342] Step G: Compounds 5-6 (55 mg, 0.19 mmol) were dissolved in dichloromethane (2.4 mL) at 0 °C. Then, 1-hydroxybenzotriazole (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), N,N-diisopropylethylamine (46 mg, 0.36 mmol), and IA (44 mg, 0.12 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give compound 5 (14.59 mg). MS(ESI)M / Z:600.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.62(t,J=5.8Hz,1H),9.11(s,1H),8.79(d,J=1.6Hz,1H),8.62(d,J= 1.2Hz,1H),8.30(d,J=9.2Hz,1H),8.20(d,J=9.2Hz,1H),7.52(s,1H),7.21(d,J=8.0Hz,1H), 6.98(d,J=8.0Hz,1H),4.77(d,J=6.0Hz,2H),4.54(t,J=5.6Hz,2H),4.32-4.23(m,4H),4.00( t,J=6.2Hz,2H),2.60-2.51(m,2H),2.06-1.96(m,1H),0.91-0.82(m,2H),0.81-0.76(m,2H).

[0343] Example 6 Preparation of Compound 6

[0344] Step A: Under nitrogen protection at room temperature, compound 6-1 (4 g, 15.75 mmol) was dissolved in 1,4-dioxane (105 mL). Then, (4-methoxyphenyl)methanethiol (2.9 g, 18.9 mmol), tris(dibenzylacetone)dipalladium (1.4 g, 1.58 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (910 mg, 1.58 mmol), and N,N-diisopropylethylamine (8.1 g, 63.0 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 120 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was quenched with water (200 mL). The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and washed with saturated brine (100 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 6-2 (4 g). MS (ESI) M / Z: 328.2 [M+H] + .

[0345] Step B: Under nitrogen protection at room temperature, compound 6-2 (4 g, 12.8 mmol) was dissolved in anisole (31.4 mL). Trifluoroacetic acid (31.4 mL) was then added dropwise to the solution. The reaction mixture was stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was quenched with water (50 mL). The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6-3 (630 mg). MS (ESI) M / Z: 208.2 [M+H] + .

[0346] Step C: Compound 6-3 (630 mg, 3.04 mmol) was dissolved in N,N-dimethylformamide (15 mL) at room temperature. Then, 1,3-dibromopropane (676 mg, 3.34 mmol) and cesium carbonate (2.4 g, 7.6 mmol) were added sequentially to the above solution. The reaction mixture was then stirred for 4 hours. The reaction mixture was quenched with ice water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 6-4 (80 mg). MS (ESI) M / Z: 248.2 [M+H] + .

[0347] Step D: Compound 6-4 (80 mg, 0.32 mmol) was dissolved in dichloromethane (3.2 mL) under nitrogen protection at room temperature. The reaction mixture was then cooled to 0 °C, and m-chloroperoxybenzoic acid (165 mg, 0.96 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6-5 (80 mg). MS (ESI) M / Z: 280.2 [M+H] + .

[0348] Step E: Compound 6-5 (80 mg, 0.29 mmol) was dissolved in tetrahydrofuran (0.7 mL), methanol (0.35 mL), and water (0.35 mL) at room temperature. Sodium hydroxide (23 mg, 0.58 mmol) was then added to the solution. The reaction mixture was stirred for 2 hours. The reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-6 (80 mg). MS (ESI) M / Z: 266.2 [M+H] + .

[0349] Step F: Compound 6-6 (36 mg, 0.14 mmol) was dissolved in dichloromethane (2.1 mL) under nitrogen protection at room temperature. The reaction mixture was then cooled to 0 °C, and 1-hydroxybenzotriazole (20 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol), N,N-diisopropylethylamine (41 mg, 0.32 mmol), and IA (35 mg, 0.11 mmol) were added sequentially to the solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (20 mL). The mixture was extracted with dichloromethane (10 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give compound 6 (15.4 mg). MS(ESI)M / Z:581.2[M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.43(t,J=5.8Hz,1H),9.10(s,1H),8.58(d,J=1.2Hz,1H),8.37-8.26(m, 2H),8.20(d,J=9.2Hz,1H),7.64(d,J=3.2Hz,1H),7.48(s,1H),7.20(d,J=8.0Hz,1H),6.97(d,J= 8.0Hz,1H),6.78(d,J=3.2Hz,1H),4.75(d,J=5.6Hz,2H),4.69-4.56(m,2H),4.37-4.20(m,4H),3 .88(t,J=6.8Hz,2H),2.47-2.36(m,2H),2.05-1.96(m,1H),0.92-0.83(m,2H),0.83-0.74(m,2H).

[0350] Example 7 Preparation of Compound 7

[0351] Operating steps:

[0352] Compound ID (30 mg, 0.046 mmol, purity: 55%) and compound 6-6 (0.012 g, 0.046 mmol) were dissolved in ultradry tetrahydrofuran (2 mL) at room temperature. Then, ethyl diisopropylamine (0.018 g, 0.14 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (0.021 g, 0.069 mmol) were added sequentially, and the mixture was stirred at room temperature for 18 hours. Compound 7 (6.7 mg) was then prepared by reverse-phase reaction (100% water - 40% acetonitrile / water). MS (ESI) M / Z: 604.2 [M+H] + . 1 HNMR(400MHz,MeOH-d4)δ9.27(d,J=0.9Hz,1H),8.65(d,J=8.7Hz,1H),8.58–8.48( m,3H),8.40(d,J=1.6Hz,1H),7.94(d,J=1.2Hz,1H),7.53–7.44(m,2H),6.76(d,J=3 .2Hz,1H),4.93(s,2H),4.76–4.68(m,2H),4.23(qd,J=7.0,2.5Hz,3H),3.79(t,J= 7.1Hz,2H),2.53(dt,J=12.3,7.0Hz,3H),2.21–2.16(m,1H),1.50(t,J=7.0Hz,3H).

[0353] Example 8 Preparation of compounds 8A and 8B

[0354] Step A: Compound 5-4 (330 mg, 1.24 mmol) was dissolved in acetonitrile (6.2 mL) under nitrogen protection at 0 °C. Subsequently, diethylaminotrifluoride (40 mg, 0.25 mmol) and a selective fluorine reagent (439 mg, 1.24 mmol) were added to the above solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-1 (186 mg). MS (ESI) M / Z: 301.2 [M+H] + .

[0355] Step B: Compound 8-1 (186 mg, 0.62 mmol) was dissolved in tetrahydrofuran (1.0 mL), methanol (0.5 mL), and water (0.5 mL) at 0 °C. Sodium hydroxide (50 mg, 1.24 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with water (10 mL) and adjusted to pH 4 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8-2 (180 mg). MS (ESI) M / Z: 287.2 [M+H] + .

[0356] Step C: Compound 8-2 (180 mg, 0.63 mmol) was dissolved in methanol (3.0 mL) and water (1.5 mL) at 0 °C. Subsequently, potassium persulfate complex salt (70693-62-8, 1.16 g, 1.89 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8-3 (130 mg). MS (ESI) M / Z: 301.0 [MH] - .

[0357] Step D: Compound 8-3 (105 mg, 0.35 mmol) was dissolved in dichloromethane (1.8 mL) at 0 °C. Then, 1-hydroxybenzotriazole (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol), N,N-diisopropylethylamine (136 mg, 1.05 mmol), and IA hydrochloride (129 mg, 0.35 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was quenched with water (15 mL). The mixture was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, followed by preparative high performance liquid chromatography and chiral separation (chiral column: Daicel AS (25*250mm, 10um), mobile phase: carbon dioxide / [ethanol / acetonitrile = 1 / 1] = 60 / 40) to obtain compound 8A (11mg) and compound 8B (14mg).

[0358] Compound 8A: SFC RT = 2.148 min, ee% = 100%. MS (ESI) M / Z: 618.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.66(t,J=5.8Hz,1H),9.11(s,1H),8.89(s,1H),8.68(d,J=0.8Hz,1 H),8.30(d,J=9.2Hz,1H),8.20(d,J=9.2Hz,1H),7.53(s,1H),7.21(d,J=8.0Hz,1H),6.98(d, J=8.0Hz,1H),6.46-6.35(m,1H),4.83-4.71(m,3H),4.61-4.51(m,1H),4.35-4.24(m,4H),3. 13-2.95(m,1H),2.82-2.63(m,1H),2.06-1.96(m,1H),0.91-0.82(m,2H),0.81-0.76(m,2H).

[0359] Compound 8B: SFC RT = 2.589 min, ee% = 99.62%. MS (ESI) M / Z: 618.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.67(t,J=5.6Hz,1H),9.11(s,1H),8.89(s,1H),8.68(d,J=0.8Hz,1H ),8.30(d,J=9.2Hz,1H),8.20(d,J=9.2Hz,1H),7.53(s,1H),7.21(d,J=8.0Hz,1H),6.98(d,J =8.0Hz,1H),6.46-6.35(m,1H)),4.82-4.71(m,3H),4.60-4.51(m,1H),4.33-4.24(m,4H),3. 12-2.96(m,1H),2.80-2.64(m,1H),2.06-1.96(m,1H),0.91-0.82(m,2H),0.80-0.76(m,2H).

[0360] Example 9 Preparation of compounds 9A and 9B

[0361] Step A: 4-4 (300 mg, 1.2 mmol) was dissolved in ultradry acetonitrile / dichloromethane (6 mL / 2 mL) at room temperature. The system became clear. After purging with nitrogen, the mixture was cooled to -5°C, and diethylaminotrifluoride (0.08 mL, 0.6 mmol) was added dropwise. Then, a selective fluorine reagent (424.8 mg, 1.2 mmol) was added and stirred. The system was poured into ice water, and then saturated sodium bicarbonate solution was added. Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by pre-TLC (ethyl acetate / petroleum ether = 1:2) to give compound 9-1 (150 mg). MS (ESI) M / Z: 267.2 [M+H] + .

[0362] Step B: Compound 9-1 (80 mg, 0.3 mmol) was dissolved in methanol / water (1 mL / 1 mL) at room temperature, followed by the addition of potassium persulfate complex salt (70693-62-8, 0.55 g, 0.9 mmol). The system was stirred at this temperature for 16 hours. The reaction was quenched with saturated sodium sulfite solution (2 mL), followed by extraction with dichloromethane (5 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by pre-TLC (ethyl acetate / petroleum ether = 1:1) to give compound 9-2 (68 mg). MS (ESI) M / Z: 299.1 [M+H] +

[0363] Step C: Compound 9-2 (68 mg, 0.23 mmol) was dissolved in tetrahydrofuran / methanol / water (1 mL / 0.5 mL / 1 mL) at room temperature, followed by the addition of lithium hydroxide hydrate (48 mg, 1.15 mmol). The system was stirred at room temperature for 2 hours. The pH was adjusted to less than 4 with 1 M dilute hydrochloric acid, followed by extraction with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 9-3 (50 mg). MS (ESI) M / Z: 285.1 [M+H] + .

[0364] Step D: 9-3 (50 mg) was purified by SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [carbon dioxide-methanol (0.1% ammonia)]; methanol ratio: 60%, isocratic elution mode) to obtain compound 9-4A (17 mg) and compound 9-4B (17 mg).

[0365] Compound 9-4A: SFC RT = 0.750 min, ee%: 99.9%, MS (ESI) M / Z: 285.0 [M+H] + .

[0366] Compound 9-4B: SFC RT = 0.942 min, ee%: 98.4%, MS (ESI) M / Z: 285.0 [M+H] + .

[0367] Step E: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.20 mg, 89.71 μmol) was added to a solution of pyridine (1 mL) of 9-4A (17 mg, 59.80 μmol) and IE (23.08 mg, 59.80 μmol). The reaction mixture was then stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 57-Phenomenex Gemini NX C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225 formic acid)-acetonitrile]; acetonitrile gradient: 43%-73%) to give compound 9A (8.2 mg). MS (ESI) M / Z: 616.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.30(s,1H),8.80(d,J=1.25Hz,1H),8.67(d,J=1.26Hz,1H),8.65-8.61(m,1H),8.59-8.55(m,1H),8.33( s,1H),7.98(s,1H),7.89(d,J=7.53Hz,1H),7.71(t,J=8.03Hz,1H),6.94(d,J=8.53Hz,1H),6.09-5.92(m ,1H),5.14-5.04(m,1H),4.95(s,2H),4.64-4.56(m,1H),4.34-4.26(m,2H),3.76(ddd,J=10.42,6.27,2. 38Hz,2H),3.18-3.05(m,1H),2.68-2.60(m,1H),2.55(dd,J=12.67,10.67Hz,2H),1.28(d,J=6.02Hz,6H).

[0368] Step F: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.20 mg, 89.71 μmol) was added to a pyridine (1 mL) solution of compound 9-4B (17 mg, 59.80 μmol) and IE (23.08 mg, 59.80 μmol). The reaction mixture was then stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 57-Phenomenex Gemini NX C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile gradient: 43%-73%) to give compound 9B (6.7 mg). MS (ESI) M / Z: 616.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.30(s,1H),8.81(d,J=1.25Hz,1H),8.67(d,J=1.25Hz,1H),8.65-8.62(m,1H),8.60-8.56(m,1H),8.33(s,1H),7.98(s,1H),7.90(d,J=7. 53Hz,1H),7.71(t,J=7.91Hz,1H),6.94(d,J=8.53Hz,1H),6.09-5.91(m,1H),5.09(ddd,J=15.00,9.98,2.38Hz,1H),4.96(s,2H),4.60(br s,1H),4.31(br d,J=11.54Hz,2H),3.84-3.69(m,2H),3.19-3.03(m,1H),2.69-2.60(m,1H),2.55(dd,J=12.67,10.67Hz,2H),1.28(d,J=6.27Hz,6H).

[0369] Example 10: Preparation of Compound 10

[0370] Operating steps:

[0371] Step A: Methyl 7-bromo-1H-indole-5-carboxylic acid (5 g, 19.68 mmol) was dissolved in trifluoroacetic acid (20 mL), and triethylsilane (4.58 g, 39.36 mmol) was added dropwise. The mixture was stirred at 60 °C for 5 hours. After cooling to room temperature, the reaction solution was concentrated by rotary evaporation to obtain the residue, which was diluted with water (20 mL) and the pH adjusted to 8-9 with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (80 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by silica gel column chromatography (ethyl acetate / n-hexane = 15%) to give compound 10⁻¹ (4.4 g). MS (ESI) M / Z: 257.9 [M + 2 + H] + . 1 H NMR (400MHz, CDCl3) ppm 7.92 (d, J = 0.8Hz, 1H), 7.67 (d, J = 1.3Hz, 1H), 3.86 (s, 3H), 3.73 (t, J = 8.7Hz, 2H), 3.26-3.11 (m, 2H).

[0372] Step B: At 0°C, m-chloroperoxybenzoic acid (11.12 g, 51.54 mmol, 80% purity) was added fractionally to a methanol (50 mL) solution of compound 10⁻¹ (4.4 g, 17.18 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with a saturated sodium thiosulfate aqueous solution (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 20%) to obtain compound 10⁻² (1.9 g). MS (ESI) M / Z: 271.9 [M + 2 + H] + . 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.24(d,J=1.3Hz,1H),7.85(d,J=1.3Hz,1H),7.65(d,J=3.5Hz,1H),6.58(d,J=3.5Hz,1H),3.85(s,3H).

[0373] Step C: Compound 10⁻² (1 g, 3.70 mmol) and ethyl 3-sulfonylpropionate (993.76 mg, 7.41 mmol) were dissolved in dioxane (20 mL). Tris(dibenzylindeneacetone)dipalladium (339.06 mg, 370.26 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (428.48 mg, 740.52 μmol), and N,N-diisopropylethylamine (957.05 mg, 7.41 mmol) were added. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 6 hours. Afterward, the mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (ethyl acetate / n-hexane = 20%) to obtain compound 10⁻³ (420 mg). MS (ESI) M / Z: 324.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.34(s,1H),8.30(d,J=1.4Hz,1H),8.00(d,J=1.3Hz,1H),7.33(d,J=3.3Hz,1H),6.47(d,J= 3.5Hz,1H),4.15-4.10(m,2H),3.94-3.90(m,3H),3.19(t,J=6.6Hz,2H),2.53(t,J=6.6Hz,2H),1.26-1.21(m,3H).

[0374] Step D: Compound 10⁻³ (420 mg, 1.30 mmol, 77% purity) and 1,2-dibromoethane (488.01 mg, 2.60 mmol) were dissolved in DMF solution (5 mL), and cesium carbonate (846.38 mg, 2.60 mmol) was added. The mixture was stirred at 50 °C for 12 hours. The reaction solution was extracted with ethyl acetate (30 mL × 3) and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 22%) to obtain compound 10⁻⁴ (90 mg). MS (ESI) M / Z: 250.6 [M + H] + . 1 H NMR (400MHz, CDCl3) δ8.12(d,J=1.3Hz,1H),7.82(d,J=1.2Hz,1H),7.23(d,J=3.5Hz, 1H), 6.40 (d, J = 3.6Hz, 1H), 4.60 (t, J = 6.0Hz, 2H), 3.92 (s, 3H), 3.49 (t, J = 6.0Hz, 2H).

[0375] Step E: Compound 10⁻⁴ (80 mg, 320.92 μmol) was dissolved in a mixture of tetrahydrofuran (1.6 mL) and methanol (0.8 mL), and lithium hydroxide (2 M, 1.60 mL) was added. The mixture was stirred at 25 °C for 6 hours. The reaction mixture was diluted with 5 mL of water, the aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid, and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10⁻⁵ (72 mg). MS (ESI) M / Z: 236.0 [M + H] + .

[0376] Step F: Compound 10⁻⁵ (72 mg, 306.05 μmol) was dissolved in a mixture of methanol (1 mL) and water (1 mL), and potassium persulfate complex salt (70693-62-8, 188.14 mg, 306.05 μmol) was added. The mixture was stirred at 25 °C for 8 hours. The reaction solution was quenched with a saturated sodium thiosulfate aqueous solution. The pH was adjusted to 2 with 1 M hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 10⁻⁶ (82 mg). MS (ESI) M / Z: 268.0 [M + H] + . 1H NMR (400MHz, MeOH-d4) δ 8.54 (s, 1H), 8.39 (s, 1H), 7.62 (d, J = 3.5Hz, 1H), 6.69 (d, J = 3.5Hz, 1H), 4.81 (t, J = 6.1Hz, 2H), 4.05 (t, J = 6.1Hz, 2H).

[0377] Step G: Compound 10-6 (21.64 mg, 80.99 μmol) and IA (27 mg, 80.99 μmol) were dissolved in pyridine (2 mL) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.29 mg, 121.48 μmol) was added. The mixture was stirred at 50 °C for 1 hour. The reaction solution was extracted with ethyl acetate (30 mL × 3) and washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by reverse-phase purification (column: 52-Welch Xtimate C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 25%-55%) to obtain compound 10 (15 mg). MS (ESI) M / Z: 583.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.57-9.38(m,1H),9.10(s,1H),8.59-8.51(m,1H),8.35-8.32(m ,1H),8.32-8.27(m,1H),8.23-8.16(m,1H),7.84(d,J=3.5Hz,1H),7.52-7.44(m,1H),7. 20(d,J=8.1Hz,1H),7.02-6.90(m,1H),6.76(d,J=3.5Hz,1H),4.79-4.72(m,4H),4.30-4 .25(m,4H),4.25-4.20(m,2H),2.04-1.97(m,1H),0.89-0.83(m,2H),0.80-0.74(m,2H).

[0378] Example 11 Preparation of compounds 11A and 11B

[0379] Operating steps:

[0380] Step A: Sodium hydroxide (94.51 mg, 2.36 mmol, 60% purity) was added to a 5 mL solution of N,N-dimethylformamide (330 mg, 1.18 mmol) at 0 °C under nitrogen atmosphere, and the mixture was stirred for 0.5 h. Then, 294.21 μL of methyl iodide (4.73 mmol) was added at 0 °C. The reaction mixture was then stirred at 25 °C for 12 h. The reaction mixture was quenched by adding 50 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluting buffer: 0-38% ethyl acetate / hexane) to obtain compound 11-1 (180 mg). MS (ESI) M / Z: 294.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.60(d,J=1.55Hz,1H),8.55(d,J=1.43Hz,1H),7.18(d,J=3.10Hz,1H),6.68(d,J=3.22Hz,1H),4.73-4.68(m,2H),3.97 (s,3H),3.67(q,J=7.55Hz,1H),2.67(dtd,J=15.18,7.64,7.64,5.07Hz,1H),2.12-1.98(m,1H),1.51(d,J=7.15Hz,3H).

[0381] Step B: At 0°C, sodium hydroxide (49.09 mg, 1.23 mmol) was added to a solution of compound 11-1 (180 mg, 613.63 μmol) in tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL). The reaction mixture was then stirred at 25°C for 12 hours. The reaction mixture was diluted with 3 mL of water at 25°C and washed with ethyl acetate (3 mL × 2). The aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid solution and extracted with ethyl acetate (3 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11-2 (160 mg). MS (ESI) M / Z: 280.0 [M+H] + .

[0382] Step C: Compound 11-2 (160 mg) was purified by SFC preparation (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: [carbon dioxide - methanol (0.1% ammonia)]; methanol: 60%, isocratic elution mode) to obtain compound 11-3A (60 mg) and compound 11-3B (62 mg).

[0383] Compound 11-3A: SFC RT = 0.948 min, ee% = 100%. MS (E SI) M / Z: 279.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.66(d,J=1.43Hz,1H),8.62(d,J=1.31Hz,1H),7.21(d,J=3.22Hz,1H),6.72(d,J=3.22Hz,1H),4.74-4.72(m, 1H),4.72(d,J=2.86Hz,1H),3.72-3.64(m,1H),2.74-2.62(m,1H),2.11-2.03(m,1H),1.53(d,J=7.15Hz,3H).

[0384] Compound 11-3B: SFC RT = 1.354 min, ee% = 99.61%. MS (ESI) M / Z: 279.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.66(d,J=1.43Hz,1H),8.62(d,J=1.43Hz,1H),7.21(d,J=3.22Hz,1H),6.71(d,J=3.22Hz,1H),4.74-4.72(m,1H ), 4.71 (d, J = 2.62Hz, 1H), 3.69 (q, J = 7.35Hz, 1H), 2.74-2.63 (m, 1H), 2.09-2.04 (m, 1H), 1.52 (d, J = 7.15Hz, 3H).

[0385] Step D: To a solution of compound 11-3A (30.00 mg, 107.41 μmol) in dichloromethane (3 mL), 1-hydroxybenzotriazole (17.42 mg, 128.89 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.71 mg, 128.89 μmol), N,N-diisopropylethylamine (46.77 μL, 268.52 μmol), and IA (39.72 mg, 107.41 μmol, hydrochloride) were added. The reaction mixture was then stirred at 25 °C for 12 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 57-Phenomenex Gemini NX C18 150×30 mm, 5 μm; mobile phase: [O1-water (0.225% formic acid)-acetonitrile]; acetonitrile gradient: 23%-53%) to give compound 11A (15.29 mg). MS (ESI) M / Z: 595.2 [M+H] + .1 H NMR(400MHz,DMSO-d6)δppm 9.43(t,J=5.90Hz,1H),9.10(s,1H),8.59(d,J=1.31Hz,1H),8.33-8.27(m,2H),8.19(d,J=9.30Hz,1H),7.64( d,J=3.10Hz,1H),7.48(s,1H),7.20(d,J=8.11Hz,1H),6.97(d,J=8.11Hz,1H),6.77(d,J=3.10Hz,1H),4.74(br d,J=5.72Hz,2H),4.67-4.58(m,2H),4.26(s,4H),3.89(q,J=7.23Hz,1H),2.68-2.58(m ,1H),2.04-1.90(m,2H),1.36(d,J=7.03Hz,3H),0.89-0.83(m,2H),0.82-0.76(m,2H).

[0386] Step E: To a solution of compound 11-3B (30.00 mg, 107.41 μmol) in dichloromethane (3 mL), 1-hydroxybenzotriazole (17.42 mg, 128.89 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.71 mg, 128.89 μmol, 1.2 eq), N,N-diisopropylethylamine (46.77 μL, 268.52 μmol), and IA (35.9 mg, 107.41 μmol) were added. The reaction mixture was then stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 57-Phenomenex Gemini NX C18 150×30 mm, 5 μm; mobile phase: [O1-water (0.225% formic acid)-acetonitrile]; acetonitrile gradient: 23%-53%) to give compound 11B (13.41 mg). MS (ESI) M / Z: 595.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.43(br t,J=5.78Hz,1H),9.10(s,1H),8.59(d,J=1.19Hz,1H),8.35-8.25(m,2H),8.19(d,J=9.30Hz,1H),7.64(d,J =3.10Hz,1H),7.48(s,1H),7.19(d,J=8.11Hz,1H),6.97(d,J=8.11Hz,1H),6.77(d,J=3.10Hz,1H),4.74(br d,J=5.72Hz,2H),4.64(br d,J=4.41Hz,2H),4.26(s,4H),3.93-3.83(m,1H),2.68-2.58(m,1H),2.04- 1.93(m,2H),1.36(d,J=6.91Hz,3H),0.90-0.83(m,2H),0.81-0.75(m,2H).

[0387] Example 12 Preparation of compounds 12A and 12B

[0388] Operating steps:

[0389] Step A: Compound 1-7 (535 mg, 2.15 mmol) was dissolved in acetonitrile (6 mL) under nitrogen protection at 0 °C. Then, diethylaminosulfur trifluoride (142.34 μL, 1.08 mmol) and a selective fluorine reagent (763.30 mg, 2.15 mmol) were added to the above solution. The reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 12-1 (540 mg); MS (ESI) M / Z: 267.1 [M+H] + .

[0390] Step B: Compound 12-1 (540 mg, 2.03 mmol) was dissolved in methanol (6.0 mL) and water (3 mL) at 0 °C. Subsequently, potassium persulfate complex salt (70693-62-8, 925.73 mg, 6.08 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-100% ethyl acetate / n-hexane) to give compound 12-2 (200 mg). MS (ESI) M / Z: 299.0 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δppm 8.66(d,J=1.31Hz,1H),8.52(d,J=1.31Hz,1H),8.44(s,1H),6.08-5.87(m,1H),4.96-4.91(m, 1H), 4.73 (ddd, J=14.87, 6.82, 2.38Hz, 1H), 4.00 (s, 3H), 3.17-3.00 (m, 1H), 2.67-2.47 (m, 1H). 19 F NMR(376MHz,MeOH-d4)δppm-170.14(s,1F).

[0391] Step C: Compound 12-2 (195 mg, 653.73 μmol) was dissolved in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL) at 0 °C. Sodium hydroxide (52.29 mg, 1.31 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with water (3 mL) and adjusted to pH 4 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The product was then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was then separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10µm); mobile phase [CO2-methanol:acetonitrile = 1:1 (0.1% ammonia)]; methanol / acetonitrile ratio: 60%) to obtain compound 12-3A (60mg, Rt = 0.523min) and compound 12-3B (62mg, Rt = 1.151min). MS (ESI) M / Z: 285.0 [M+H] + .

[0392] Step D: Compound 12-3A or 12-3B (30 mg, 105.54 μmol, parallel batch) and ID (49.75 mg, 126.64 μmol, 1.2 eq, HCl) were dissolved in pyridine (1.5 mL). Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.35 mg, 158.30 μmol) was added sequentially to the above solution. The reaction system was then stirred at 50 °C for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (column: 57-Phenomenex Gemini NX C18 150 × 30 mm, 5 μm; mobile phase: [O1-water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 42%-72%, 8.0 min) to give compound 12A (36 mg) or compound 12B (26 mg).

[0393] Compound 12A: MS (ESI) M / Z: 623.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)9.24(s,1H),8.71-8.39(m,6H),7.93(s,1H),7.47(d,J= 8.78Hz,1H),6.08-5.88(m,1H),4.98-4.91(m,3H),4.78-4.69(m,1H),4.21(br dd,J=6.90,2.38Hz,2H),3.29-3.22(m,1H),3.17-3.02(m,1H),2.68-2.49(m,2H),1.97-1.84(m,1H),1.49(t,J=6.90Hz,3H). 19 F NMR (376MHz, MeOH-d4) -126.68 (br d, J = 152.59Hz, 2F), -145.39 (br d, J = 149.12Hz, 1F).

[0394] Compound 12B: MS (ESI) M / Z: 623.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)9.25(s,1H),8.70-8.42(m,6H),7.94(s,1H),7.48(d,J=8.78Hz,1H),6.10-5.88(m,1H),4.98-4.90(m,3H),4.7 9-4.70(m,1H),4.27-4.16(m,2H),3.29-3.23(m,1H),3.17-2.99(m,1H),2.57-2.50(m,2H),1.95-1.83(m,1H),1.50(t,J=6.90Hz,3H). 19 F NMR (376MHz, MeOH-d4) -126.69 (br d, J = 149.12Hz, 2F), -145.39 (br d, J = 149.12Hz, 1F).

[0395] Example 13 Preparation of compounds 13A and 13B

[0396] Step A: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59.61 mg, 310.97 μmol) was added to a pyridine (1 mL) solution of compound 8-3 (62.66 mg, 207.31 μmol) and compound IE (80 mg, 207.31 μmol). The reaction mixture was then stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-50% ethyl acetate / hexane) to obtain 80 mg of crude product. The crude product was purified by SFC (column: 101-DAICEL CHIRALPAK IM 250 × 30 mm, 10 μm; mobile phase: [carbon dioxide-ethanol]; ethanol ratio: 60%) to obtain compound 13A (19.8 mg) and compound 13B (21.4 mg).

[0397] Compound 13A: SFC RT = 4.139 min. ee%: 100%. MS (ESI) M / Z: 634.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.33-9.26(m,1H),8.73(d,J=6.32Hz,2H),8.65-8.61(m,1H),8.59-8.54(m,1H),7.98(s,1H),7.89(d, J=7.39Hz,1H),7.71(t,J=7.93Hz,1H),6.94(d,J=8.46Hz,1H),6.10-5.94(m,1H),4.94(s,2H),4.92(br s,1H),4.63-4.55(m,1H),4.30(br d,J=12.40Hz,2H),3.81-3.72(m,2H),3.16-3.00(m,1H),2.76-2.60(m,1H),2.59-2.48(m,2H),1.28(d,J=6.20Hz,6H).

[0398] Compound 13B: SFC RT = 5.263 min. ee%: 99.7%. MS (ESI) M / Z: 634.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δppm 9.34-9.25(m,1H),8.73(d,J=7.27Hz,2H),8.66-8.62(m,1H),8.59-8.55(m,1H),7.98(s,1H),7.90(d,J=7.27Hz,1H),7.7 1(t,J=7.93Hz,1H),6.94(d,J=8.34Hz,1H),6.10-5.95(m,1H),4.95(s,2H),4.93-4.90(m,1H),4.63-4.55(m,1H),4.31(br d,J=11.68Hz,2H),3.82-3.72(m,2H),3.17-3.01(m,1H),2.77–2.61(m,1H),2.55(dd,J=12.52,10.73Hz,2H),1.28(d,J=6.20Hz,6H).

[0399] Example 14 Preparation of compounds 14A and 14B

[0400] Operating steps:

[0401] Step A: Compound 12-3A or compound 12-3B (30 mg, 105.54 μmol, parallel batch) and compound IE (44.80 mg, 116.09 μmol, hydrochloride) were dissolved in pyridine (1.5 mL). Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.35 mg, 158.30 μmol) was added sequentially to the above solution. The reaction system was then stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (column: 57-Phenomenex Gemini NX C18 150×30 mm, 5 μm; mobile phase: [O1-water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 30%-60%) to obtain compound 14A (25 mg) and compound 14B (28 mg).

[0402] Compound 14A: SFC (Column: Chiralpak AD-3 50×4.6mm ID, 3µm, Mobile phase A: CO2; B: Ethanol (0.2% ammonia-methanol, B phase ratio: 50%), RT = 1.660 min, ee%: 100%, MS (ESI) M / Z: 616.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.63(t,J=5.84Hz,1H),9.40(s,1H),8.76(d,J=1.31Hz,1H),8.69-8.60(m,2H),8.57(s,1H),8.47(d,J=1.19Hz,1H),7.90(d,J=7.39Hz, 1H),7.84(s,1H),7.72(t,J=7.93Hz,1H),7.02(d,J=8.58Hz,1H),6.39-6.21(m,1H),4.85(d,J=5.60Hz,2H),4.79-4.66(m,2H),4.31(br d,J=11.21Hz,2H),3.67(ddd,J=10.31,6.20,2.44Hz,2H),3.11-2.97(m,1H),2.68-2.52(m,2H),2.48-2.44(m,1H),1.21(d,J=6.32Hz,6H). 19 F NMR(376MHz,DMSO-d6)δppm-169.72(s,1F).

[0403] Compound 14B: SFC (Column: Chiralpak AD-3 50×4.6mm ID, 3µm, Mobile phase A: CO2; B: Ethanol (0.2% ammonia-methanol, B phase ratio: 40%), RT = 3.139 min, ee%: 98.74, MS (ESI) M / Z: 616.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.63(t,J=5.84Hz,1H),9.40(s,1H),8.76(d,J=1.31Hz,1H),8.60-8.70(m,2H),8.57(s,1H),8.47(d,J=1.19Hz,1H ),7.90(d,J=7.39Hz,1H),7.84(s,1H),7.72(t,J=7.99Hz,1H),7.02(d,J=8.58Hz,1H),6.39-6.20(m,1H),4.85(br d,J=5.60Hz,2H),4.79-4.65(m,2H),4.31(br d,J=11.56Hz,2H),3.72-3.62(m,2H),3.11-2.97(m,1H),2.68-2.52(m,2H),2.48-2.44(m,1H),1.21(d,J=6.20Hz,6H). 19 F NMR(376MHz,DMSO-d6)δppm-169.72(s,1F).

[0404] Example 15 Preparation of Compound 15

[0405] Operating steps:

[0406] Step A: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.69 mg, 128.78 μmol) was added to a pyridine (0.5 mL) solution of compound IE (23.98 mg, 85.85 μmol) and compound 11-3B (30 mg, 85.85 μmol). The reaction mixture was then stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 57-Phenomenex Gemini NX C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile gradient: 43%-73%) to give compound 15 (12.9 mg). MS (ESI) M / Z: 611.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.49(t,J=6.02Hz,1H),9.40(s,1H),8.69-8.62(m,2H),8.61(d,J=1.25Hz,1H),8.32(d,J=1.25Hz,1H),7.89(d,J=7.53 Hz,1H),7.80(s,1H),7.75-7.69(m,1H),7.64(d,J=3.01Hz,1H),7.02(d,J=8.53Hz,1H),6.78(d,J=3.26Hz,1H),4.82(br d,J=5.52Hz,2H),4.68-4.59(m,2H),4.31(br d,J=11.54Hz,2H),3.93-3.85(m,1H),3.72-3.61(m,2H),2.69-2.57(m,1H),2.55 -2.51(m,2H),2.02-1.91(m,1H),1.37(d,J=7.03Hz,3H),1.21(d,J=6.27Hz,6H).

[0407] Example 16 Preparation of Compound 16

[0408] Operating steps:

[0409] Step A: Under nitrogen protection, sodium hydride (3.2 g, 80.28 mmol, 60% purity) was dissolved in anhydrous tetrahydrofuran (50 mL). At 0°C, an anhydrous tetrahydrofuran solution containing compound IA-2 (4.0 g, 13.38 mmol) (10 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 5 minutes, followed by the dropwise addition of acetyl chloride (6.3 g, 80.28 mmol). The reaction mixture was then brought to room temperature and the reaction continued for 12 hours. The reaction mixture was cooled to 0°C, and methanol (7.5 mL) and water (7.5 mL) were added. The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were concentrated under reduced pressure. The crude product was dissolved in tetrahydrofuran (15 mL) and water (10 mL), and lithium hydroxide monohydrate (0.34 g, 8.03 mmol) was added. The reaction mixture was stirred for another half hour. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give compound 16-1 (2.4 g). MS (ESI) M / Z: 341.0 [M+H] + .

[0410] Step B: 16-1 (330 mg, 0.97 mmol), (2-((tert-butyldimethylsilyl)oxy)ethyl)(prop-2-yn-1-yl)carbamate tert-butyl ester (0.30 g, 0.97 mmol), and triethylamine (0.98 g, 9.7 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Cuprous iodide (18 mg, 0.097 mmol) and palladium dichloride bis(triphenylphosphine) (0.068 g, 0.097 mmol) were added. The reaction mixture was reacted at room temperature for 12 hours under nitrogen protection. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was concentrated under reduced pressure. The reaction mixture was also concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give compound 16-2 (410 mg). MS (ESI) M / Z: 526.2 [M+H] + .

[0411] Step C: Compound 16-2 (410 mg, 0.78 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (0.030 g, 0.16 mmol) was added. The reaction solution was heated to 80°C and reacted for 0.5 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phase was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 16-3 (260 mg). MS (ESI) M / Z: 484.2 [M+H] + .

[0412] Step D: Compound 16-3 (320 mg, 0.66 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (0.26 g, 0.99 mmol, 1 M) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 16-4 (200 mg). MS (ESI) M / Z: 370.1 [M + H] + .

[0413] Step E: Under nitrogen protection, compound 16-4 (150 mg, 0.41 mmol) and triphenylphosphine (0.16 g, 0.61 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and diisopropyl azodicarbonate (0.12 g, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 16-5 (140 mg). MS (ESI) M / Z: 352.1 [M+H] + .

[0414] Step F: Under nitrogen protection, zinc powder (5.6 mg, 0.086 mmol) was added to a solution of N,N-dimethylacetamide (5 mL) containing compound 16-5 (150 mg, 0.43 mmol) and zinc cyanide (0.10 g, 0.86 mmol), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.070 g, 0.086 mmol). The reaction mixture was purged with nitrogen three times, then heated to 120°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 16-6 (90 mg). MS (ESI) M / Z: 299.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.92 (s, 1H), 7.71 (s, 1H), 6.53 (s, 1H), 4.89 (s, 2H), 4.19 (t, J = 6.0Hz, 2H), 3.99 (t, J = 6.0Hz, 2H), 1.51 (s, 9H).

[0415] Step G: Compound 16-6 (90 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL, 13.46 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was adjusted to pH 9 with ammonia. The solution was then diluted with ethyl acetate / methanol (V... 10 / 1 Extracted by extraction (50 mL), the organic phase was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 16-7 (47 mg). MS (ESI) M / Z: 199.1 [M+H] + .

[0416] Step H: Under nitrogen protection, compound 16-7 (30 mg, 0.15 mmol), IE-2 (49 mg, 0.18 mmol), and cesium carbonate (240 mg, 0.75 mmol) were dissolved in 1,4-dioxane (5 mL) solution. Then, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (17 mg, 0.030 mmol) and tris(dibenzylacetone)dipalladium (14 mg, 0.015 mmol) were added. The reaction mixture was purged with nitrogen three times, then heated to 100°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 16-8 (50 mg). MS (ESI) M / Z: 389.2 [M+H] + .

[0417] Step I: Under nitrogen protection, compound 16-8 (50 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL). The reaction solution was cooled to -70°C, and diisobutylaluminum hydride (0.046 g, 0.33 mmol) was slowly added dropwise. The reaction solution was stirred at -70°C for 2 hours. The reaction solution was quenched in an ice-cold saturated ammonium chloride solution, and extracted with dichloromethane (50 mL × 2). The combined organic phases were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane / methanol / 0.1% ammonia = 20 / 1 / 1) to give compound 16-9 (30 mg). MS (ESI) M / Z: 393.2 [M+H] + .

[0418] Step J: Compound IB (25 mg, 0.091 mmol), 1-hydroxybenzotriazole (15 mg, 0.11 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22 mg, 0.11 mmol) were dissolved in dichloromethane (5 mL), and the mixture was stirred for 10 minutes. Then, 16-9 (30 mg, 0.076 mmol) and N,N-diisopropylethylamine (29 mg, 0.23 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2), and the combined organic phases were concentrated under reduced pressure. The crude product was preparatively separated by prep-HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: phase B from 42% to 72%) to obtain compound 16 (10.3 mg). MS(ESI)M / Z:653.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.45(t,J=5.8Hz,1H),8.71(s,1H),8.32–8.23(m,2H ),7.42–7.34(m,2H),6.45(s,1H),6.34–6.24(m,1H),6.28–6.11(m,2H),4.88 (s,2H),4.69–4.56(m,3H),4.19–4.01(m,7H),3.58(ddd,J=10.5,6.3,2.4Hz, 2H),2.89–2.58(m,2H),2.33(dd,J=12.7,10.5Hz,2H),1.16(d,J=6.2Hz,6H).

[0419] Example 17 Preparation of compounds 17A and 17B

[0420] Operating steps:

[0421] Step A: Sulfuric acid (43.50 μL, 816.08 μmol) was added to a mixture of compound 1-3 (2 g, 8.16 mmol) and triethyl orthoacetate (4.49 mL, 24.48 mmol) in methanol (20 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, then stirred with ethyl acetate (20 mL) for 1 hour, filtered, and the filter cake was dried to give compound 17-1 (2.4 g). MS (ESI) M / Z: 269.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=1.31Hz,1H),8.01(d,J=1.19Hz,1H),3.89(s,3H),2.65(s,3H).

[0422] Step B: Compound 17-1 (2.2 g, 8.18 mmol) was dissolved in 1,4-dioxane (25 mL) under nitrogen protection at 25 °C. Then, (4-methoxyphenyl)methanethiol (1.14 mL, 8.18 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (473.05 mg, 817.56 μmol), tris(dibenzylacetone)dipalladium (748.65 mg, 817.56 μmol), and N,N-diisopropylethylamine (5.70 mL, 32.70 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 120 °C for 4 hours. The reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined and washed with saturated brine (60 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting buffer: 0-100% ethyl acetate / n-hexane, 35 mL / min) to give compound 17-2 (2.29 g). MS (ESI) M / Z: 343.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ12.67(s,1H),8.02-7.82(m,1H),7.72-7.61(m,1H),7.29-7.16( m,2H),6.86-6.79(m,2H),4.42-4.20(m,2H),3.84(s,3H),3.70(s,3H),2.57-2.52(m,3H).

[0423] Step C: Under nitrogen protection at room temperature, compound 17-2 (2.25 g, 6.57 mmol) was dissolved in trifluoroacetic acid (25 mL). The reaction mixture was then stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 17-3 (1.66 g). MS (ESI) M / Z: 223.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.94-7.91 (m, 1H), 7.89 (d, J = 1.19Hz, 1H), 3.86 (s, 3H), 2.66 (s, 3H).

[0424] Step D: Compound 17-3 (1.66 g, 7.47 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 0 °C. Then, 1,3-dibromopropane (1.14 mL, 11.20 mmol) and potassium carbonate (4.13 g, 29.87 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at room temperature for 4 hours. The reaction solution was quenched with water (60 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the combined organic phases were washed with saturated brine (60 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0-100% ethyl acetate / n-hexane, 35 mL / min) to give compound 17-4 (78 mg). MS (ESI) M / Z: 263.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 1.00Hz, 1H), 7.60 (d, J = 1.25Hz, 1H), 4.57-4. 50(m,2H),3.83(s,3H),3.30(t,J=6.53Hz,2H),2.54(s,3H),2.39-2.32(m,2H).

[0425] Step E: Compound 17-4 (970 mg, 3.70 mmol) was dissolved in acetonitrile (15 mL) under nitrogen protection at 0 °C. Subsequently, diethylaminosulfur trifluoride (244.27 μL, 1.85 mmol) and a selective fluorine reagent (1.31 g, 3.70 mmol) were added to the above solution. The reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 17-5 (1 g). MS (ESI) M / Z: 281.1 [M+H] + .

[0426] Step F: Compound 17-5 (1 g, 3.57 mmol) was dissolved in methanol (10 mL) and water (5 mL) at 0 °C. Subsequently, potassium persulfate complex salt (70693-62-8, 1.63 g, 10.70 mmol) was added to the above solution. The reaction mixture was then stirred at room temperature for 16 hours. The reaction solution was quenched with water (50 mL). The mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined and washed with saturated brine (40 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-100% ethyl acetate / n-hexane) to give compound 17-6 (630 mg). MS (ESI) M / Z: 313.1 [M+H] + .

[0427] Step G: Compound 17-6 (630 mg, 2.02 mmol) was dissolved in tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL) at 0 °C. Sodium hydroxide (161.36 mg, 4.03 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with water (5 mL) and adjusted to pH 4 with 2 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 17-7 (420 mg) was obtained and separated into compound 17-8A (200 mg) and compound 17-8B (201 mg) by SFC (chiral column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [carbon dioxide-ethanol (0.1% ammonia)]; ethanol ratio: 45%).

[0428] Compound 17-7: MS (ESI) M / Z: 299.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.28(s,1H),6.35-6.19(m,1H),4.67-4.49(m,2H),3.06-2.93(m,1H),2.65(s,3H),2.61-2.52(m,1H). 19 F NMR(376MHz,DMSO-d6)δppm-169.42(br s,1F).

[0429] Compound 17-8A: SFC RT = 0.856 min, ee% = 100%;

[0430] Compound 17-8B: SFC RT=2.189min, ee%=100%.

[0431] Step H: Compound 17-8A or 17-8B (25 mg, 83.81 μmol, parallel feed) and compound IE (35.58 mg, 92.19 μmol) were dissolved in pyridine (1.5 mL). Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.10 mg, 125.72 μmol) was added sequentially to the above solution. The reaction system was then stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (column: 57-Phenomenex Gemini NX C18 150×30 mm, 5 μm; mobile phase: [O1-water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 35%-65%) to obtain compound 17A (30 mg) and compound 17B (29 mg).

[0432] Compound 17A: SFC (column: Chiralpak OD-3 50×4.6mm ID, 3µm, mobile phase A: carbon dioxide; B: ethanol (0.2% ammonia-methanol), B phase ratio: 40%), RT = 1.795 min, ee% = 100%. MS (ESI) M / Z: 630.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.61(br t,J=5.78Hz,1H),9.40(s,1H),8.68-8.58(m,3H),8.40(d,J=1.19Hz,1H),7.90(d,J=7.39Hz, 1H),7.83(s,1H),7.72(t,J=7.93Hz,1H),7.02(d,J=8.46Hz,1H),6.37-6.19(m,1H),4.84(br d,J=5.60Hz,2H),4.67-4.51(m,2H),4.31(br d,J=11.68Hz,2H),3.72-3.62(m,2H),3.10-2.93(m,1H),2.66(s,3H),2.60-2.52(m,2H),2.48-2.44(m,1H),1.21(d,J=6.20Hz,6H). 19 F NMR(376MHz,DMSO-d6)δ-169.40(s,1F).

[0433] Compound 17B: SFC (Column: Chiralpak OD-3 50×4.6mm ID, 3µm, Mobile phase A: CO2; B: Ethanol (0.2% ammonia-methanol), B phase ratio: 40%) RT = 1.973 min, ee% = 100%. MS (ESI) M / Z: 630.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.61(br t,J=5.78Hz,1H),9.40(s,1H),8.69-8.58(m,3H),8.40(s,1H),7.90(d,J=7.39Hz,1H), 7.83(s,1H),7.72(t,J=7.93Hz,1H),7.02(d,J=8.46Hz,1H),6.36-6.19(m,1H),4.84(br d,J=5.48Hz,2H),4.68-4.51(m,2H),4.30(br d,J=11.92Hz,2H),3.74-3.62(m,2H),3.09-2.94(m,1H),2.66(s,3H),2.62-2.52(m,2H),2.48-2.44(m,1H),1.21(d,J=6.20Hz,6H). 19 F NMR(376MHz,DMSO-d6)δ-169.40(s,1F).

[0434] Example 18 Preparation of Compound 18

[0435] Operating steps:

[0436] Step A: To a mixture of compound 18-1 (48.73 mg, 374.47 μmol), IC (100 mg, 340.43 μmol), and dioxane (5 mL), tridibenzylacetone dipalladium (31.17 mg, 34.04 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (39.40 mg, 68.09 μmol), and cesium carbonate (332.75 mg, 1.02 mmol) were added, and the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched in water (30 mL), and the crude product was extracted with ethyl acetate (30 mL × 2). The crude product was then subjected to rapid silica gel column chromatography (eluting buffer: 0-80% ethyl acetate / hexane) to obtain compound 18-2 (58 mg). MS (ESI) M / Z: 388.2 [M+H] + .

[0437] Step B: 2 mL of dioxane hydrochloride solution was added to compound 18-2 (100 mg, 258.13 μmol), and the reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. Compound 18-3 (75 mg) was obtained. MS (ESI) M / Z: 288.1 [M+H] + .

[0438] Step C: To a pyridine (2 mL) solution of compound 18-3 (30.32 mg, 105.54 μmol), 1-ethyl-(3-dimethylaminopropyl))carbodiimide hydrochloride (21.92 mg, 114.33 μmol) and compound 9-4B (25 mg, 87.95 μmol) were added. The reaction mixture was then stirred at 50 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The residue was then subjected to preparative-grade HPLC (column: 20-Welch Xtimate C18 250×50 mm; mobile phase: [O1-water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile gradient: 35%-65%) to give compound 18 (15.1 mg). MS (ESI) M / Z: 554.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δ9.56(s,1H),8.86-8.71(m,2H),8.69-8.57(m,2H),8 .39-8.26(m,2H),8.20(s,1H),6.13-5.88(m,1H),5.15-4.97(m,3H),4.84(br s,2H),4.47(q,J=7.0Hz,2H),3.19-3.00(m,1H),2.70-2.49(m,1H),1.48(t,J=7.0Hz,3H).

[0439] Example 19 Preparation of Compound 19

[0440] Operating steps:

[0441] Step A: Potassium phosphate (4.67 g, 14.32 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) chloride (139.41 mg, 213.90 μmol) were added to a solution of compound IE-2 (580 mg, 2.14 mmol) and potassium trifluoro(vinyl)borate (573.04 mg, 4.28 mmol) in dioxane (5 mL) and water (1 mL). The mixture was then stirred at 80 °C for 2 hours. The reaction mixture was quenched in water (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-10% ethyl acetate / hexane) to give compound 19-1 (200 mg). MS(ESI)M / Z:219.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ7.44(t,J=7.9Hz,1H),6.78-6.64(m,2H),6.56(d,J=8.3Hz,1H),6.24(dd,J=1.7,17.3Hz,1H),5.40(dd,J=1.5,10.6Hz,1H),4.16(br d,J=12.0Hz,2H),3.76(ddd,J=2.4,6.2,10.6Hz,2H),2.54(dd,J=10.7,12.5Hz,2H),1.30(d,J=6.3Hz,6H).

[0442] Step B: To a solution of compound 19-1 (100 mg, 458.10 μmol) in N,N-dimethylformamide (3 mL), tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate (197.32 mg, 687.15 μmol), tri-o-tolylphosphine (34.86 mg, 114.52 μmol), palladium acetate (10.28 mg, 45.81 μmol), and triethylamine (177.62 mg, 1.37 mmol, 239.38 μL) were added, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched in water (30 mL) and extracted with ethyl acetate (20 mL × 2). After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting with 0-80% ethyl acetate / hexane) to give compound 19-2 (136 mg). MS(ESI)M / Z:425.2[M+H] + . 1H NMR (400MHz, CDCl3) δ=8.50-8.41(m,1H),7.47-7.35(m,2H),7.35-7.30(m,1H),7.24(br d,J=3.9Hz,1H),7.17-6.98(m,2H),6.67(d,J=7.2Hz,1H),6.52(d,J=8.5Hz,1H),4.40(br d,J=5.4Hz,2H),4.14-4.03(m,2H),3.68(ddd,J=2.4,6.3,10.4Hz,2H),2.50(dd,J=10.7,12.5Hz,2H),1.44-1.39(m,9H),1.27-1.16(m,6H).

[0443] Step C: Add 3 mL of dioxane hydrochloride solution to compound 19-2 (100 mg, 235.55 μmol), and then stir the reaction mixture at 25 °C for 12 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product, compound 19-3 (75 mg, hydrochloride). MS (ESI) M / Z: 325.2 [M+H] + .

[0444] Step D: To a pyridine (2 mL) solution of compound 19-3 (27.39 mg, 84.43 μmol), 1-ethyl-(3-dimethylaminopropyl))carbodiimide hydrochloride (17.53 mg, 91.46 μmol) and 9-4B (20 mg, 70.36 μmol) were added. The reaction mixture was then stirred at 50 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The residue was then subjected to preparative-grade HPLC (column: 20-Welch Xtimate C18 250 × 50 mm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile gradient: 28%-58%) to give compound 19 (12.2 mg, hydrochloride). MS (ESI) M / Z: 591.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δ8.80(s,1H),8.78(d,J=6.1Hz,1H),8.57(s,1H),8.34(s,1H),8.30(s,1H),8.22-8.12(m,2H),8.00(br t,J=8.1Hz,1H),7.80(br d,J=16.3Hz,1H),7.52-7.39(m,2H),6.12-5.91(m,1H),5.01(s,3H),4.87-4.74(m,2H),4.28(br d,J=12.9Hz,2H),3.86-3.71(m,2H),3.19-3.02(m,1H),2.92(br t,J=11.7Hz,2H),2.67-2.50(m,1H),1.28(d,J=6.1Hz,6H).

[0445] Example 20 Preparation of Compound 20

[0446] Operating steps:

[0447] Step A: To a triethylamine (45 mL) solution of compound 2-bromo-6-chloronicotinaldehyde (3.2 g, 14.52 mmol), palladium dichloride bis(triphenylphosphine) chloride (1.02 g, 1.45 mmol) and cuprous iodide (138.23 mg, 725.78 μmol) were added, followed by the addition of compound 20-1 (3.16 g, 17.42 mmol). The mixture was purged with nitrogen three times. Under nitrogen atmosphere, the reaction solution was stirred at 70 °C for 5 hours. After cooling to room temperature, the reaction solution was quenched in water (100 mL), then extracted with dichloromethane (200 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate: n-hexane eluent) to obtain compound 20-2 (2.55 g). 1 H NMR (400MHz, CDCl3) δppm 10.44(s,1H),8.12(d,J=8.23Hz,1H),7.40-7.36(m,1H),5.27-5.08(m,1H),1.50(s,9H),1.47-1.44(m,2H),1.33-1.28(m,2H).

[0448] Step B: Ammonium acetate (919.16 mg, 11.92 mmol) and silver trifluoromethanesulfonate (408.52 mg, 1.59 mmol) were added to a tert-butanol (30 mL) solution of compound 20-2 (2.55 g, 7.95 mmol). The reaction mixture was stirred at 20°C for 2 hours. The reaction was quenched by pouring the mixture into a saturated aqueous solution of sodium bicarbonate (30 mL), and then extracted with ethyl acetate (90 mL × 3). The organic layers were combined, washed with saturated brine (90 mL), and the organic layer was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate: n-hexane eluent) to obtain compound 20-3 (1.21 g). MS (ESI) M / Z: 320.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δppm 9.18(s,1H),8.44(d,J=8.58Hz,1H),7.82(s,1H),7.56(d,J=8.58Hz,1H),1.73-1.68(m,2H),1.52(s,9H),1.34-1.32(m,2H).

[0449] Step C: The mixture of compound 20-3 (0.55 g, 1.72 mmol), compound IE-2 (1.2 g, 3.38 mmol), and palladium dichloride bis(triphenylphosphine) (120.72 mg, 171.99 μmol) in dioxane (12 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 100°C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–30% ethyl acetate: n-hexane eluent) to obtain compound 20-4 (652.6 mg). MS (ESI) M / Z: 476.2 [M+H] + .

[0450] Step D: Dissolve 50 mg, 0.1 mmol in ethyl acetate (1 mL) at room temperature, then add ethyl acetate hydrochloride (2 mL) solution dropwise. Stir the system at room temperature for 2 hours. Concentrate the system directly to remove the solvent to obtain compound 20-5 hydrochloride (30 mg). MS (ESI) M / Z: 376.2 [M+H] + .

[0451] Step E: Compound IB (23 mg, 0.083 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (37 mg, 0.12 mmol) were dissolved in ultradry tetrahydrofuran (5 mL) at room temperature. Then, ethyl diisopropylamine (41 μl) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (37 mg, 0.12 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 20 (35 mg) was prepared by reverse-phase reaction (100% water - 40% acetonitrile / water). MS (ESI) M / Z: 636.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.78(s,1H),9.32(s,1H),8.68-8.53(m,2H),8.42-8.35(m,2H),7.87(d,J=7.4Hz, 1H),7.81-7.67(m,2H),7.01(d,J=8.5Hz,1H),6.29(ddd,J=43.9,5.6,2.0Hz,1H),4.63(dt,J=13.0,3.9Hz, 1H),4.30(dd,J=12.9,2.4Hz,2H),4.18(t,J=12.0Hz,1H),3.76-3.63(m,2H),2.83(dt,J=38.5,13.7Hz,1H ), 2.61 (d, J = 16.2Hz, 1H), 2.46 (s, 2H), 1.73 (q, J = 4.0Hz, 2H), 1.41 (q, J = 4.1Hz, 2H), 1.21 (d, J = 6.2Hz, 6H).

[0452] Example 21 Preparation of Compound 21

[0453] Operating steps:

[0454] Compound 20-5 (31 mg, 0.083 mmol) and compound 9-4B (24 mg, 0.083 mmol) were dissolved in ultradry tetrahydrofuran (5 mL) at room temperature. Then, ethyl diisopropylamine (41 μl) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (37 mg, 0.12 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 21 (16 mg) was prepared by reverse-phase reaction (100% water-40% acetonitrile / water). MS (ESI) M / Z: 643.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.33(s,1H),8.97(s,1H),8.69-8.50(m,4H),7.89-7.78( m,2H),7.68(t,J=7.9Hz,1H),7.00(d,J=8.5Hz,1H),6.38(dt,J=45.6,5.9Hz,1H),5.02-4.73( m,2H),4.30(d,J=12.4Hz,2H),3.66(ddd,J=14.8,7.2,3.9Hz,2H),3.14-3.01(m,1H),2.64(s, 2H), 1.99 (p, J = 7.2Hz, 1H), 1.75 (q, J = 4.2Hz, 2H), 1.44 (q, J = 4.3Hz, 2H), 1.21 (d, J = 6.1Hz, 6H).

[0455] Example 22 Preparation of compounds 22A and 22B

[0456] Operating steps:

[0457] Step A: To a solution of methyl 7-bromo-1H-indole-5-carboxylic acid (4.7 g, 18.50 mmol) in acetonitrile (30 mL) and pyridine (15 mL), a selective fluorine reagent (CAS: 140681-55-6, 9.83 g, 27.75 mmol) was added. The reaction mixture was then stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative-grade HPLC (column: 50-Welch Xtimate C18 150 × 40 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 40%-70%) to give compound 22-1 (1.2 g). MS (ESI) M / Z: 272.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),8.12(s,1H),7.13(s,1H),3.96(s,3H).

[0458] Step B: To a mixture of compound 22-1 (1.2 g, 4.41 mmol), ethyl 3-mercaptopropionate (1.18 g, 8.82 mmol), and dioxane (12 mL), tris(dibenzylacetone)dipalladium (201.94 mg, 220.53 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (255.21 mg, 441.06 μmol), and N,N-diisopropylethylamine (1.14 g, 8.82 mmol, 1.54 mL) were added under nitrogen protection. The mixture was then stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography (eluting buffer: 0-15% ethyl acetate / hexane) to give compound 22-2 (1.75 g). MS (ESI) M / Z: 326.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.40 (s, 1H), 8.09 (d, J = 1.2Hz, 1H), 7.14 (t, J = 2.8Hz, 1H), 4.2 1(q,J=7.2Hz,2H),3.95(s,3H),3.14(t,J=6.8Hz,2H),2.62-2.56(m,2H),1.30(t,J=7.2Hz,3H).

[0459] Step C: Cesium carbonate (5.26 g, 16.14 mmol) was added to a solution of compound 22-2 (1.75 g, 5.38 mmol) and 1,3-dibromopropane (1.09 g, 5.38 mmol, 548.44 μL) in N,N-dimethylformamide (18 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched in water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-15% ethyl acetate / hexane) to give compound 22-3 (1.1 g). MS (ESI) M / Z: 266.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.17(d,J=1.2Hz,1H),7.81-7.77(m,1H),6.81(d,J=3.2Hz ,1H),4.63-4.55(m,2H),3.92(s,3H),3.36(t,J=6.8Hz,2H),2.44-2.37(m,2H).

[0460] Step D: At 25°C under a nitrogen atmosphere, a selective fluorine reagent (CAS: 140681-55-6, 320.47 mg, 904.63 μmol) was added to a solution of compound 22-3 (200 mg, 753.86 μmol) and diethylaminosulfur trifluoride (49.80 μL, 376.93 μmol) in acetonitrile (4 mL) and dichloromethane (1.5 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was quenched dropwise by adding 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 22-4 (200 mg).

[0461] Step E: At 0°C, potassium persulfate complex salt (70693-62-8, 1.30 g, 2.12 mmol) was added to a methanol (5 mL) and water (2.5 mL) solution of compound 22-4 (200 mg, 705.98 μmol), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluting buffer: 0-30% ethyl acetate / hexane) to obtain compound 22-5 (50 mg). MS (ESI) M / Z: 316.1 [M+H] + .

[0462] Step F: Sodium hydroxide (12.69 mg, 317.17 μmol) was added to a solution of compound 22-5 (50 mg, 158.58 μmol) in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL) at 25 °C. The reaction mixture was then stirred at 25 °C for 3 hours. The reaction mixture was diluted with water (3 mL) at 25 °C, the aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid, and extracted with ethyl acetate (3 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 22-6 (45 mg). MS (ESI) M / Z: 302.0 [M+H] + .

[0463] Step G: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.98 mg, 213.79 μmol) was added to a pyridine (1 mL) solution of 22-6 (42.94 mg, 142.53 μmol) and compound IE (55 mg, 142.53 μmol). The reaction mixture was then stirred at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative-grade HPLC (column: 52-Welch Xtimate C18 150 × 30 mm, 5 μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile ratio: 60%-90%). Compound 22A (2.8 mg) and compound 22B (2.6 mg) were then separated by SFC (column: DAICEL CHIRALPAK IK (250 mm * 25 mm, 10 μm); mobile phase: [carbon dioxide - ethanol (0.1% ammonia)]; ethanol (0.1% ammonia): 50%).

[0464] Compound 22A: SFC:RT=2.838min; ee%:99.21%. MS (ESI) M / Z:633.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δppm 9.31(s,1H),8.66-8.62(m,2H),8.60-8.56(m,1H),8.51(s,1H),7.98(s,1H),7.90(d,J=7.28Hz,1H),7.72 (t,J=8.03Hz,1H),7.43(d,J=2.76Hz,1H),6.94(d,J=8.53Hz,1H),6.03-5.85(m,1H),4.95(s,2H),4.79(br d,J=2.26Hz,1H),4.53-4.43(m,1H),4.34-4.27(m,2H),3.82-3.71(m,2H),3.07-2.94(m,1H),2.55(br dd,J=12.67,10.4Hz,2H),2.51-2.44(m,1H),1.28(d,J=6.02Hz,6H).

[0465] Compound 22B: SFC:RT = 3.284 min; ee%: 96.87%. MS (ESI) M / Z: 633.1 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.31(s,1H),8.67-8.57(m,3H),8.51(d,J=1.26Hz,1H),7.98(s,1H),7.91(d,J=7.53Hz,1H),7.72(t,J=7.91Hz,1H),7.43 (d,J=2.76Hz,1H),6.95(d,J=8.78Hz,1H),6.01-5.83(m,1H),4.95(s,2H),4.83-4.82(m,1H),4.53-4.43(m,1H),4.31(br d,J=11.80Hz,2H),3.82-3.72(m,2H),3.09-2.91(m,1H),2.55(dd,J=12.42,10.67Hz,2H),2.52-2.42(m,1H),1.29(d,J=6.27Hz,6H).

[0466] Example 23 Preparation of compounds 23A and 23B

[0467] Operating steps:

[0468] Step A: At room temperature, BOC anhydride (1.93 mL, 8.42 mmol) and triethylamine (1.95 mL, 14.03 mmol) were added to a solution of compound 23-a (1 g, 7.01 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluent: n-hexane / ethyl acetate, 0-50%) to give compound 23-b (1.4 g). MS (ESI) M / Z: 243.1 [M+H] + .

[0469] Step B: Under a nitrogen atmosphere, potassium acetate (363.93 mg, 3.71 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (104.63 mg, 123.61 μmol) were added sequentially to a solution of 23-b (300 mg, 1.24 mmol) and pinacol diboronate (376.67 mg, 1.48 mmol) in 6 mL of 1,4-dioxane. The reaction mixture was heated to 80 °C and stirred for 2 hours. The solvent was then removed by filtration and rotary evaporation under reduced pressure and used directly in the next step. MS (ESI) M / Z: 253.1 [M+H] + .

[0470] Step C: At room temperature, (2S,6R)-2,6-dimethylmorpholine (2.83 g, 24.57 mmol) was added to a solution of 6-fluoropyridinium (3 g, 24.57 mmol) and potassium carbonate (10.19 g, 73.71 mmol) in NN,dimethylformamide (60 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluent: n-hexane / ethyl acetate, 0-20%) to give compound 23-1 (4.92 g). MS (ESI) M / Z: 218.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.58-7.49(m,1H),6.99(d,J=7.28Hz,1H),6.80(d,J=8.78Hz,1H),4.25-4.01(m,2H),3.69 (ddd,J=10.29,6.40,2.38Hz,2H),2.57(dd,J=12.55,10.79Hz,2H),1.28(d,J=6.02Hz,6H).

[0471] Step D: Under nitrogen protection, at -78°C, diisobutylaluminum hydride (1M, 56.38mL) was slowly added dropwise to a tetrahydrofuran (100mL) solution of compound 23-1 (4.9g, 22.55mmol). The reaction mixture was then heated to 0°C and stirred for 1 hour. Under nitrogen protection, the reaction mixture was quenched with a saturated sodium potassium tartrate tetrahydrate solution (100mL) and extracted with ethyl acetate (100mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (eluent: n-hexane / ethyl acetate, 0-15%) to give compound 23-2 (1.04g). MS (ESI) M / Z: 221.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.92(s,1H),7.64(t,J=7.91Hz,1H),7.29(d,J=7.03Hz,1H),6.85(d,J=8.28Hz,1H),4.14-4.23(m,2H),3. 74(dqd,J=10.46,6.30,6.30,6.30,2.51Hz,2H),2.59(dd,J=12.67,10.67Hz,2H),1.30(d,J=6.27Hz,6H).

[0472] Step E: Under a nitrogen atmosphere at 0°C, diethylzinc (1M, 7.08mL) was slowly added dropwise to a tetrahydrofuran (20mL) solution of compound 23-2 (1.04g, 4.72mmol), tribromofluoromethane (1.92g, 7.08mmol), and triphenylphosphine (1.86g, 7.08mmol). The reaction mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (15mL) and extracted with ethyl acetate (20mL × 3). The organic phase was washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to rapid silica gel column chromatography (eluent: n-hexane / ethyl acetate, 0-15%) for compound 23-3 (630mg). MS (ESI) M / Z: 315.0 [M+H] + .

[0473] Step F: Under a nitrogen atmosphere, potassium carbonate (460.44 mg, 3.33 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (90.69 mg, 111.05 μmol) were added sequentially to a mixed solution of dioxane (10 mL) and water (2 mL) of compound 23-3 (350 mg, 1.11 mmol) and compound 23-c (307.91 mg, 1.22 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to rapid silica gel column chromatography (eluent: n-hexane / ethyl acetate, 0-50%) to give compound 23-4 (300 mg). MS (ESI) M / Z: 443.2 [M+H] + .

[0474] Step G: Dissolve 23-4 (300 mg, 677.93 μmol) in dioxane hydrochloride (2 M, 12.00 mL) and stir at 20 °C for 2 hours. The reaction solution was directly concentrated without purification to obtain compound 23-5 hydrochloride (256 mg). MS (ESI) M / Z: 343.2 [M+H] + .

[0475] Step G: To a pyridine (2 mL) solution of compound 9-4B (50 mg, 175.89 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.58 mg, 263.84 μmol), 23-5 hydrochloride (66.64 mg, 175.89 μmol) was added, and the reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was preparatively separated by high performance liquid chromatography (column: 44-Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile; acetonitrile ratio: 43%-73%) to obtain compound 23A (19.04 mg) and compound 23B (10.59 mg).

[0476] Compound 23A: HPLC RT = 4.667 min; MS (ESI) M / Z: 609.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.54(br t,J=5.77Hz,1H),8.86(s,1H),8.62(d,J=5.02Hz,1H),8.58(s,1H),8.54-8.45(m,1H),7.79-7.57 (m,3H),7.14(d,J=7.28Hz,1H),6.96-6.77(m,2H),6.45-6.24(m,1H),5.00-4.87(m,1H),4.78(br d,J=6.27Hz,1H),4.69(br d,J=5.77Hz,2H),4.19(br d,J=12.05Hz,2H),3.67-3.55(m,2H),3.15-2.93(m,1H),2.66-2.56(m,1H),2.43-2.35(m,2H),1.15(d,J=6.02Hz,6H).

[0477] Compound 23B: HPLC RT = 4.384 min; MS (ESI) M / Z: 609.2 [M+H] + . 1¹H NMR (400MHz, DMSO-d⁶) δppm 9.52-9.39(m,1H),8.76(s,1H),8.66-8.57(m,1H),8.54-8.42(m,2H),7.44- 7.28(m,3H),6.71-6.63(m,1H),6.62-6.57(m,1H),6.50(d,J=8.53Hz,1H),6. 45-6.26(m,1H),5.01-4.70(m,2H),4.66-4.54(m,2H),3.48-3.34(m,4H),3.1 5-2.97(m,1H),2.66-2.56(m,1H),2.09-1.91(m,2H),0.98(d,J=6.02Hz,6H).

[0478] Example 24 Preparation of Compound 24

[0479] Operating steps:

[0480] Step A: Diethylaminosulfur trifluoride (2.38 g, 14.74 mmol, 1.95 mL) was added to a mixed solution of compound 5-4 (7.85 g, 29.48 mmol) in acetonitrile (150 mL) and dichloromethane (75 mL) to obtain a mixed solution. This mixture was slowly added to a flask containing a selective fluorine reagent (12.56 g, 35.45 mmol) under nitrogen protection, and the mixture was stirred at 20 °C for 2 hours. The reaction solution was quenched by slowly pouring saturated sodium bicarbonate aqueous solution (150 mL) at 25 °C and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-A (7.2 g). MS (ESI) M / Z: 285.1 [M+H] + . 1 HNMR(400MHz,CDCl3)δppm 8.31(d,J=0.8Hz,1H),8.06(d,J=1.2Hz,1H),6.22-5.98(m,1H),4.86(ddd,J=1.6,9.2,14.4H z,1H),4.44(ddd,J=2.0,8.4,14.8Hz,1H),3.94(s,3H),3.09-2.93(m,1H),2.90-2.74(m,1H).

[0481] Step B: Potassium persulfate complex salt (46.7 g, 75.96 mmol) was added to a mixed solution of 24-A (7.2 g, 25.33 mmol, 1 eq) in methanol (140 mL) and water (70 mL) at 0 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was obtained by passing it through a rapid silica gel column (eluting with 0-20% ethyl acetate / hexane). The crude product was passed through an SFC (column: DAICL CHIRALPAK IG (250 mm * 50 mm, 10 μm); mobile phase: [carbon dioxide-ethanol (0.1% ammonia)]; gradient: 25%) to obtain compound 24-B1 (2.4 g) and compound 24-B2 (2.3 g).

[0482] Compound 24-B1: SFC RT = 2.876 min; ee% = 100%; MS (ESI) M / Z: 317.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.81(d,J=1.2Hz,1H),8.74(d,J=1.2Hz,1H),5.72(td,J=5.6,46.4Hz,1H),5.01(ddd,J=2.4,9.6,1 4.8Hz,1H),4.57(ddd,J=2.8,7.8,14.8Hz,1H),4.01(s,3H),3.15-3.00(m,1H),2.75-2.61(m,1H).

[0483] Compound 24-B2: SFC RT = 3.070 min; ee% = 99.65%; MS (ESI) M / Z: 317.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.76(s,1H),8.49(d,J=1.2Hz,1H),6.54-6.31(m,1H),4.85-4.70(m,1H),4. 57(td,J=6.8,8.4Hz,1H),3.94(s,3H),3.13-2.94(m,1H),2.80-2.62(m,1H).

[0484] Step C: At 20°C, a solution of sodium hydroxide (580 mg, 14.50 mmol) in water (10 mL) was added to a mixed solution of tetrahydrofuran (20 mL) and methanol (10 mL) of compound 24-B2 (2.3 g, 7.27 mmol). The mixture was stirred at 20°C for 0.5 hours. The pH was adjusted to 4 with 1 M hydrochloric acid aqueous solution. Extraction was performed with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 24-C (2.28 g). MS (ESI) M / Z: 303.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm13.64(br s,1H),8.72(d,J=1.2Hz,1H),8.51(d,J=1.2Hz,1H),6.50-6.30(m,1H),4.76(ddd,J=2.4,9 .2,14.8Hz,1H),4.56(ddd,J=2.0,8.4,14.8Hz,1H),3.10-2.94(m,1H),2.76-2.63(m,1H).

[0485] Step D: To a solution of compound 24-1 (2 g, 6.43 mmol) and N-Boc-aminopropyne (1.20 g, 7.72 mmol) in acetonitrile (30 mL), bis(triphenylphosphine) palladium dichloride (451.50 mg, 643.26 μmol), cuprous iodide (61.25 mg, 321.63 μmol), and triethylamine (1.95 g, 19.30 mmol, 2.69 mL) was added, followed by purging with nitrogen. The mixture was then stirred at 20 °C for 1 hour under nitrogen protection. The reaction mixture was quenched with 30 mL of water, extracted with ethyl acetate (30 mL × 3), and the organic phase was separated. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (ethyl acetate / n-hexane, eluent gradient 0–13%) to obtain compound 24-2 (1.7 g). MS (ESI) M / Z: 338.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.42(s,1H),7.76(d,J=8.3Hz,1H),7.70(d,J=1.5Hz,1 H),7.58(d,J=8.3Hz,1H),4.93-4.80(m,1H),4.25-4.20(m,2H),1.48(s,9H).

[0486] Step E: Silver trifluoromethanesulfonate (194.49 mg, 756.96 μmol) was added to a solution of compound 24-2 (1.28 g, 3.78 mmol) and ammonium acetate (437.61 mg, 5.68 mmol) in tert-butanol (15 mL), purging with nitrogen. The solution was stirred at 20 °C for 2 hours under nitrogen protection. The reaction mixture was quenched with water (15 mL), followed by extraction with ethyl acetate (30 mL × 3). The organic phase was separated and washed with saturated sodium bicarbonate solution (30 mL × 3) and saturated brine (30 mL × 3), respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (ethyl acetate / petroleum ether, gradient 0–45%) to obtain compound 24-3 (1 g). MS (ESI) M / Z: 338.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 9.18 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 8.6Hz, 1H), 7.67 (dd, J = 1.7, 8.7Hz, 1H), 7.55 (s, 1H), 5.47 (br s, 1H), 4.59 (br d,J=5.7Hz,2H),1.48(s,9H).

[0487] Step F: To a dioxane solution (20 mL) of compound 24-3 (900 mg, 2.67 mmol) and pinacol diboronate (813.30 mg, 3.20 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (195.29 mg, 266.90 μmol) and potassium acetate (785.81 mg, 8.01 mmol) were added, followed by nitrogen purging. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction mixture was then quenched with water (15 mL), followed by extraction with ethyl acetate (20 mL × 3). The organic phase was separated, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–35% ethyl acetate / petroleum ether) to obtain compound 24-4 (930 mg). 1 H NMR (400MHz, CDCl3) δ = 9.21 (s, 1H), 8.31 (s, 1H), 7.94 (s, 2H), 7.66 (br s, 1H), 5.62 (br s, 1H), 4.58 (br d, J = 5.4Hz, 2H), 1.47 (s, 9H), 1.40 (s, 12H).

[0488] Step G: To a mixed solution of dioxane (4 mL) and water (1 mL) of compound 24-C (200 mg, 691.70 μmol) and compound 24-4 (292.38 mg, 760.87 μmol), palladium dichloride dichloride (48.55 mg, 69.17 μmol) and sodium carbonate (146.62 mg, 1.38 mmol) were added, and nitrogen was introduced to displace the mixture. The mixture was then stirred at 90 °C under nitrogen protection for 3 hours. The reaction mixture was quenched with water (10 mL) at 20 °C, followed by extraction with ethyl acetate (20 mL × 3). The organic phase was separated, washed with saturated brine (20 mL × 3) and the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–40% ethyl acetate / petroleum ether) to obtain compound 24-5 (140 mg). MS(ESI)M / Z:467.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ = 9.27-9.22 (m, 1H), 8.46 (br s,1H),8.31-8.25(m,1H),8.09-8.05(m,1H),7.80-7.75(m,1H),7.42(t,J=9.7Hz,1H),6.70-6.66(m,1H),5.69-5.50( m,1H),4.66-4.60(m,2H),4.12-4.08(m,2H),3.82-3.75(m,2H),2.63-2.56(m,2H),1.48(s,9H),1.33(d,J=6.2Hz,6H).

[0489] Step H: Compound 24-5 (120 mg, 257.21 μmol) was added to a hydrochloric acid / dioxane solution (2 M, 10 mL). The solution was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound 24-6 hydrochloride (70 mg), which was used directly in the next step. MS (ESI) M / Z: 367.2 [M+H] + .

[0490] Step I: To a pyridine (2 mL) solution of compound 24-C (15 mg, 49.63 μmol) and compound 24-6 hydrochloride (21.99 mg, 54.59 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.27 mg, 74.44 μmol) was added. The solution was stirred at 50 °C for 1 hour. Pyridine was removed by concentration under reduced pressure. The crude product was purified by prep-HPLC (column: 52-Welch Ultimate C18 150×30 mm, 5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; acetonitrile ratio: 45%-75%) to give compound 24 (6.6 mg). MS (ESI) M / Z: 651.3 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δ=9.26(br s,1H),8.72(d,J=4.2Hz,2H),8.47(s,1H),8.27(d,J=8.9Hz,1H),8.16(d,J=8.6 Hz,1H),7.91(s,1H),7.51(t,J=9.9Hz,1H),6.87(dd,J=2.1,9.1Hz,1H),6.10-5. 93(m,1H),4.91(s,3H),4.59-4.56(m,1H),4.19-4.15(m,2H),3.77-3.72(m,2H) ,3.11-3.04(m,1H),2.71-2.62(m,1H),2.53-2.47(m,2H),1.25(d,J=6.2Hz,6H). 19 F NMR(376MHz,MeOH-d4)δ-133.66(s,1F),-139.55(s,1F),-174.71(s,1F).

[0491] Example 25 Preparation of Compound 25

[0492] Operating steps:

[0493] Step A: A solution of compound 25-1 (1 g, 4.40 mmol), potassium cyclopropyltrifluoroborate (1.63 g, 11.01 mmol), palladium acetate (69.21 mg, 308.29 μmol), potassium phosphate (2.80 g, 13.21 mmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (308.27 mg, 660.63 μmol) in toluene (10.5 mL) and water (1.5 mL) was stirred at 110 °C under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel chromatography (elution gradient of 0–60% ethyl acetate / hexane). Compound 25-2 (527 mg) was obtained. MS (ESI) M / Z: 189.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 8.07 (d, J = 2.4Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 5.07 (br s,1H),3.59-3.49(m,2H),2.64(t,J=7.0Hz,2H),1.78-1.68(m,1H),0.89-0.81(m,2H),0.60-0.51(m,2H).

[0494] Step B: A solution of compound 25-2 (527 mg, 2.80 mmol) in dichloromethane (1 mL) and diethylaminosulfur trifluoride (6.10 g, 37.84 mmol, 5 mL) was stirred at 40 °C for 12 hours. The reaction mixture was added dropwise to a saturated sodium bicarbonate solution in ice water (35 mL), followed by extraction with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–70% ethyl acetate / hexane). Compound 25-3 (254 mg) was obtained. MS (ESI) M / Z: 211.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 7.98 (s, 1H), 7.45 (s, 1H), 4.92 (br s,1H),3.60-3.30(m,2H),2.41-2.25(m,2H),1.87-1.75(m,1H),0.97-0.86(m,2H),0.66-0.52(m,2H).

[0495] Step C: The reaction mixture of compound 25-3 (100 mg, 475.69 μmol), compound IC (167.68 mg, 570.82 μmol), tris(dibenzylacetone)dipalladium(0) (43.56 mg, 47.57 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (55.05 mg, 95.14 μmol), and cesium carbonate (464.96 mg, 1.43 mmol) in dioxane (3 mL) was stirred at 105 °C for 4 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–70% ethyl acetate / hexane). Compound 25-4 (160 mg) was obtained. MS (ESI) M / Z: 468.3 [M+H] + .

[0496] Step D: A solution of compound 25-4 (80 mg, 171.12 μmol) in hydrochloric acid / dioxane (2 M, 5.33 mL) was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 25-5 hydrochloride (65 mg). MS (ESI) M / Z: 368.2 [M+H] + .

[0497] Step 5: To a solution of compound 25-5 hydrochloride (38.77 mg, 96.01 μmol) and 9-4B (25.00 mg, 87.95 μmol) in pyridine (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.72 mg, 175.89 μmol) was added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The obtained residue was preparatively isolated to give compound 25 (20 mg). MS (ESI) M / Z: 634.1 [M+H] + . 1 H NMR (400MHz, MeOH-d4) δ = 9.38 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 8.42 (q, J = 9.5Hz, 2H ),8.35(s,1H),8.32(s,1H),8.08(s,1H),7.84(s,1H),6.15-5.88(m,1H),5.10(ddd,J =2.4,10.0,15.0Hz,1H),5.00(s,2H),4.84-4.78(m,1H),4.63-4.53(m,2H),3.20-3.0 3(m,1H),2.69-2.51(m,3H),2.14-1.98(m,1H),1.16-1.07(m,2H),0.87-0.74(m,2H).

[0498] Example 26 Preparation of Compound 26

[0499] Operating steps:

[0500] Step A: 2,4-Dichloropyrimidine (1 g, 6.71 mmol) and (2S,6R)-2,6-dimethylmorpholine (0.93 g, 8.05 mmol) were dissolved in isopropanol (20 mL) at room temperature. Then, N,N-diisopropylethylamine (1.73 g, 13.42 mmol) was added, and the mixture was stirred at 50 °C for 1 hour. The mixture was concentrated to obtain a crude product, which was then purified by column chromatography to obtain 26-2 (1 g). MS (ESI) M / Z: 228.2 [M+H] + .

[0501] Step B: Compounds 24-4 (299.53 mg, 0.78 mmol) and 26-2 (177 mg, 0.78 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) at room temperature. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (127.40 mg, 0.16 mmol) and potassium carbonate (0.32 g, 2.34 mmol) were added. The system was then purged with nitrogen and stirred at 90 °C for 3 hours. The system was directly concentrated to obtain the crude product, which was then purified by column chromatography to obtain compound 26-3 (370 mg). MS (ESI) M / Z: 450.4 [M+H] + .

[0502] Step C: Compound 26-3 (30 mg, 0.067 mmol) was dissolved in ethyl acetate (1 mL) at room temperature, followed by the dropwise addition of ethyl acetate hydrochloride solution (4 M, 2 mL). The system was stirred at room temperature for 2 hours. The system was then concentrated to remove the solvent, yielding compound 26-4 hydrochloride (25 mg). MS (ESI) M / Z: 351.2 [M+H] + .

[0503] Step D: Compound 26-4 (25 mg, 0.072 mmol) and compound 24-C (0.022 g, 0.072 mmol) were dissolved in ultradry tetrahydrofuran (2 mL) at room temperature. Then, ethyl diisopropylamine (0.028 g, 0.22 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (0.032 g, 0.11 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 26 (13 mg) was prepared by reversed-phase liquid chromatography. MS (ESI) M / Z: 634.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.62(t,J=5.8Hz,1H),9.35(s,1H),8.93(s,1H),8.88(d,J=1.5Hz,1H),8.66(d,J=1. 5Hz,1H),8.57(dd,J=8.6,1.6Hz,1H),8.38(d,J=6.1Hz,1H),8.20(d,J=8.6Hz,1H),7.99(s,1H),6.87(d,J=6 .2Hz,1H),6.39(dt,J=45.2,5.8Hz,1H),4.81(d,J=5.9Hz,2H),4.78-4.72(m,1H),4.60-4.36(m,3H),3.62(d dd,J=10.6,6.2,2.6Hz,2H),3.10-2.94(m,1H),2.77-2.65(m,1H),2.65-2.56(m,2H),1.20(d,J=6.2Hz,6H).

[0504] Example 27 Preparation of Compound 27

[0505] Operating steps:

[0506] Step A: At 0°C, cuprous iodide (6.64 g, 34.88 mmol) and tert-butyl nitrite (4.32 g, 41.86 mmol, 4.98 mL) were added to a 100 mL solution of acetonitrile containing compound 27-1 (5 g, 23.25 mmol). The mixture was stirred at 0–50°C for 12 hours. The mixture was diluted with 150 mL of ammonia, and then extracted with ethyl acetate (150 mL × 3) to separate the organic phase. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–10% ethyl acetate / petroleum ether) to give compound 27-2 (1.98 g). MS (ESI) M / Z: 400.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.60 (dd, J=8.34, 6.32Hz, 1H), 7.24 (dd, J=8.34, 1.19Hz, 1H).

[0507] Step B: Under nitrogen atmosphere, diisobutylaluminum hydride (1M, 1.84mL) was added to a solution of compound 27-2 (0.5g, 1.53mmol) in dichloromethane (10mL). The mixture was stirred at 0°C for 1 hour, and then stirred again at 20°C under nitrogen atmosphere for 1.5 hours. The mixture was quenched by slow addition of hydrochloric acid solution (20mL, 0.5M), followed by extraction with ethyl acetate (20mL × 3) to separate the organic phase. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–5% ethyl acetate / petroleum ether) to obtain compound 27-3 (400mg). 1 H NMR (400MHz, CDCl3) δppm 10.04 (s, 1H), 7.72-7.65 (m, 1H), 7.58 (dd, J=8.28, 1.00Hz, 1H).

[0508] Step C: To a 10 mL acetonitrile solution of compound 27-3 (350 mg, 1.06 mmol), N-Boc-aminopropyne (198.18 mg, 1.28 mmol), cuprous iodide (20.27 mg, 106.41 μmol), palladium dichloride bis(triphenylphosphine) (149.38 mg, 212.83 μmol), and triethylamine (323.04 mg, 3.19 mmol, 444.34 μL) were added, and nitrogen was introduced to purge the mixture. The mixture was then stirred at 20 °C for 2 hours under nitrogen atmosphere. The mixture was quenched with water (50 mL), followed by extraction with ethyl acetate (50 mL × 3) to separate the organic phase. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate / petroleum ether) to give compound 27-4 (220 mg). MS (ESI) M / Z: 378.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 10.38 (s, 1H), 7.54-7.70 (m, 2H), 4.87 (br d, J=1.25Hz, 1H), 4.27 (br d, J=5.27Hz, 2H), 1.49 (s, 9H).

[0509] Step D: To a mixture of compound 27-4 (220 mg, 617.65 μmol) and tert-butanol (5 mL), ammonium acetate (71.42 mg, 926.48 μmol) and silver trifluoromethanesulfonate (31.74 mg, 123.53 μmol) were added, and nitrogen was introduced to replace the nitrogen atmosphere. The mixture was then stirred at 25 °C for 1 hour under nitrogen. The mixture was diluted with 20 mL of saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–30% ethyl acetate / petroleum ether) to obtain compound 27-5 (150 mg). MS (ESI) M / Z: 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.27 (s, 1H), 7.94 (br s, 1H), 7.82-7.71 (m, 2H), 5.73-5.55 (m, 1H), 4.68 (br d, J = 5.77Hz, 2H), 1.49 (s, 9H).

[0510] Step E: To a 2 mL solution of compound 27-5 (140 mg, 394.14 μmol) and pinacol diborate (110.10 mg, 433.56 μmol) in dioxane, add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (43.26 mg, 59.12 μmol), potassium acetate (96.71 mg, 985.36 μmol), and purge with nitrogen. The mixture is then stirred at 90 °C under nitrogen for 2 hours. The reaction mixture is concentrated under reduced pressure to obtain compound 27-6 (125 mg), which is used directly in the next step.

[0511] Step F: To a mixture of compound 27-6 (100 mg, 248.59 μmol), compound IE-1 (73.8 mg, 273.45 μmol), dioxane (1.6 mL), and water (0.4 mL), palladium dichloride bis(triphenylphosphine) chloride (17.45 mg, 24.86 μmol), sodium carbonate (79.04 mg, 745.77 μmol) was added, and nitrogen was introduced to purge the mixture. The mixture was then stirred at 90 °C under nitrogen for 3 hours. The reaction mixture was quenched with water (10 mL) at 20 °C, followed by extraction with ethyl acetate (10 mL × 3) to separate the organic phase, which was then washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–33% ethyl acetate / petroleum ether) to obtain compound 27-7 (100 mg). MS(ESI)M / Z:467.3[M+H] + . 1H NMR (400MHz, CDCl3δ=9.27-9.23(m,1H),8.28-8.22(m,1H),7.96-7.93(m, 1H),7.86-7.82(m,1H),7.67-7.61(m,1H),7.40-7.37(m,1H),7.36-7.29( m,1H),6.71-6.66(m,1H),5.59-5.44(m,1H),4.71-4.61(m,2H),4.22-4.1 7(m,2H),3.81-3.75(m,2H),1.94-1.89(m,1H),1.49(s,9H),1.25(s,6H).

[0512] Step G: Add compound 27-7 (90 mg, 192.91 μmol) to a hydrochloric acid / dioxane solution (2 M, 5 mL). Stir the solution at 20 °C for 1 hour. Concentrate the reaction mixture under reduced pressure to remove the hydrochloric acid / dioxane, giving compound 27-8 hydrochloride (70 mg), which can be used directly in the next step. MS (ESI) M / Z: 367.0 [M+H] + .

[0513] Step H: To a pyridine (1 mL) solution of compound 24-C (30 mg, 99.25 μmol) and compound 27-8 hydrochloride (43.99 mg, 109.18 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.54 mg, 148.88 μmol) was added. The solution was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove pyridine. The crude product was purified by prep-HPLC (column: 57-Phenomenex Gemini NX C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile ratio: 50%-80%) to give compound 27 (21.27 mg). MS (ESI) M / Z: 651.3 [M+H] + . 1H NMR (400MHz, MeOH-d4) δ = 9.30 (s, 1H), 8.72 (s, 1H), 8.71 (d, J = 1.4Hz, 1H), 8.28-8.24 (m,1H),8.04(s,1H),7.98(d,J=8.8Hz,1H),7.69-7.64(m,1H),7.37-7.33(m,1H),6.8 6-6.83(m,1H),6.12-5.93(m,1H),4.94-4.91(m,3H),4.65-4.51(m,2H),4.28-4.23(m ,2H),3.78-3.71(m,2H),3.14-3.03(m,1H),2.56-2.49(m,2H),1.26(d,J=6.2Hz,6H).

[0514] Example 28 Preparation of Compound 28

[0515] Operating steps:

[0516] Step A: 2-Bromo-6-fluoropyridine (273 mg, 1.55 mmol) and (2S,6R)-1,2,6-trimethylpiperazine (0.20 g, 1.55 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. Cesium carbonate (1.52 g, 4.65 mmol) was then added, and the mixture was stirred at 80 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the mixture. After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 28-1 (320 mg). MS (ESI) M / Z: 286.1 [M + H + 2] + .

[0517] Step B: Compound 28-1 (320 mg, 1.13 mmol) and tetrakis(triphenylphosphine)palladium (0.26 g, 0.23 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Hexa-n-butylditin (0.79 g, 1.36 mmol) was then added, and the system was purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL), and the organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 28-2 (640 mg). MS (ESI) M / Z: 494.3 [M+H] + .

[0518] Step C: 28-2 (640 mg, 0.91 mmol) and compound IC (0.27 g, 0.91 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature. Then, palladium dichloride (0.13 g, 0.18 mmol) was added. The system was then purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL). The organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 28-3 (180 mg) was purified by column chromatography. MS (ESI) M / Z: 463.3 [M+H] + .

[0519] Step D: Dissolve 28-3 (30 mg, 0.065 mmol) in ethyl acetate (2 mL) at room temperature, then add dropwise ethyl acetate hydrochloride solution (4 M, 1 mL). Stir the system at room temperature for 1 hour. Concentrate the system to obtain 28-4 hydrochloride (25 mg), which is used directly in the condensation reaction. MS (ESI) M / Z: 363.2 [M+H] + .

[0520] Step E: Compound 28-4 hydrochloride (25 mg, 0.069 mmol) and compound 24-C (0.021 g, 0.069 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. Then, N,N-diisopropylethylamine (0.027 g, 0.21 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (0.031 g, 0.10 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 28 (16 mg) was prepared by reversed-phase high-performance liquid chromatography. MS (ESI) M / Z: 647.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.70(t,J=5.8Hz,1H),9.40(s,1H),8.90(d,J=1.5Hz,1H),8.70-8.58(m,3 H),7.90-7.83(m,2H),7.71(dd,J=8.5,7.4Hz,1H),7.03(d,J=8.5Hz,1H),6.40(dt,J=45.3,5.8Hz, 1H),4.85(d,J=5.7Hz,2H),4.77(ddd,J=14.9,9.0,2.4Hz,1H),4.56(dd,J=14.1,8.1Hz,1H),4.33 -4.24(m,2H),3.04(td,J=16.3,8.0Hz,2H),2.79-2.58(m,4H),2.21(s,3H),1.13(d,J=6.1Hz,6H).

[0521] Example 29 Preparation of Compound 29

[0522] Operating steps:

[0523] Step A: Potassium carbonate (2.36 g, 17.05 mmol) was added to a dimethyl sulfoxide (15 mL) solution of compound 2-bromo-6-fluoropyridine (1 g, 5.68 mmol) and (R)-3-ethoxypyrrolidine (785.33 mg, 6.82 mmol). The mixture was stirred at 100 °C for 3 hours. The reaction mixture was quenched with water (20 mL) at 20 °C, and then extracted with ethyl acetate (20 mL × 2) to separate the organic phase. The combined organic layers were washed with saturated brine (20 mL × 2) and concentrated under reduced pressure to give compound 29-1 (1.1 g), which was used directly in the next step. MS (ESI) M / Z: 272.9 [M + H + 2] + .

[0524] Step B: To a toluene (2 mL) solution of compound 29-1 (100 mg, 368.80 μmol), add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (26.98 mg, 36.88 μmol) and trimethyl(trimethylstanyl)stanane (290 mg, 885.15 μmol, 183.54 μL) and purge with nitrogen. The mixture is then stirred at 110 °C for 2 hours under nitrogen protection. The reaction mixture is filtered through diatomaceous earth and washed with ethyl acetate (5 mL). The filtrate is concentrated under reduced pressure to give compound 29-2 (130 mg), which is used directly in the next step. MS (ESI) M / Z: 357.1 [M+H] + .

[0525] Step C: To a solution of compound 29-2 (126.92 mg, 357.45 μmol) and compound IC (100 mg, 340.43 μmol) in dioxane (3 mL), palladium dichloride bis(triphenylphosphine) chloride (23.89 mg, 34.04 μmol) was added, and nitrogen was introduced to purge the mixture. The mixture was then stirred at 100 °C under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography (0–55% ethyl acetate / petroleum ether) to give compound 29-3 (45 mg). MS (ESI) M / Z: 450.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 9.28-9.26 (m, 1H), 8.83 (br d,J=8.6Hz,1H),8.43-8.39(m,1H),8.15-8.08(m,1H),7.98(d,J=7.3Hz, 1H),7.69-7.65(m,1H),6.55(d,J=8.3Hz,1H),6.02-5.68(m,1H),4.75(br d,J=5.0Hz,2H),3.76(d,J=5.2Hz,1H),3.69(br s,2H),3.60(dd,J=2.4,7.0Hz,2H),2.21-2.18(m,2H),1.61-1.57(m,2H),1.47(s,9H),1.25(s,3H).

[0526] Step D: Add compound 29-3 (45 mg, 100.10 μmol) to a hydrochloric acid / dioxane solution (2 M, 10 mL). Stir the solution at 20 °C for 1 hour. Concentrate the reaction mixture under reduced pressure to remove the hydrochloric acid / dioxane, giving compound 29-4 hydrochloride (30 mg), which can be used directly in the next step. MS (ESI) M / Z: 350.3 [M+H] + .

[0527] Step E: To a pyridine (2 mL) solution of compound 24-C (15 mg, 49.63 μmol) and compound 29-4 hydrochloride (21.07 mg, 54.59 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.27 mg, 74.44 μmol) was added. The mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove pyridine, yielding a crude product. The crude product was purified by prep-HPLC (column: 52-Welch Xtimate C18 150 × 30 mm, 5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 30%-60%) to give compound 29 (6.9 mg). MS (ESI) M / Z: 634.3 [M+H] + . 1 H NMR (400MHz, MeOH-d4) δ = 9.28 (s, 1H), 8.75-8.71 (m, 2H), 8.67 (d, J = 8.8Hz, 1H), 8.54 (d, J = 8.5Hz,1H),7.97(s,1H),7.80-7.75(m,1H),7.68-7.61(m,1H),6.59(d,J=8.5Hz,1H),6.11- 5.94(m,1H),4.94(s,3H),4.61-4.56(m,1H),4.30-4.26(m,1H),3.72-3.65(m,2H),3.64-3 .55(m,4H),3.13-3.03(m,1H),2.71-2.62(m,1H),2.21-2.14(m,2H),1.21(t,J=7.0Hz,3H).

[0528] Example 30 Preparation of Compound 30

[0529] Operating steps:

[0530] Step A: Compound 30-1 (15 g, 80.82 mmol) was dissolved in carbon tetrachloride (500 mL), and N-bromosuccinimide (21.58 g, 121.22 mmol) and azobisisobutyronitrile (2.65 g, 16.16 mmol) were added. The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography (eluting buffer: 0-20% ethyl acetate / hexane) to give compound 30-2 (15 g). MS (ESI) M / Z: 263.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ = 7.87 (d, J = 8.3Hz, 1H), 7.50 (d, J = 8.3Hz, 1H), 4.89 (s, 2H), 4.03 (s, 3H).

[0531] Step B: Trimethylcyanosilane (2.75 g, 27.72 mmol, 3.47 mL) was dissolved in acetonitrile (100 mL), tetrabutylammonium fluoride (1 M, 28.36 mL) was added to the reaction mixture, and compound 30-2 (5 g, 18.90 mmol) was added to the reaction mixture. The mixture was then purged with nitrogen three times, and the reaction mixture was stirred at 20-25 °C for 5 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-25% ethyl acetate / hexane) to give compound 30-3 (1.8 g). MS (ESI) M / Z: 210.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 7.98 (d, J = 8.3Hz, 1H), 7.59 (d, J = 8.3Hz, 1H), 4.26 (s, 2H), 4.01 (s, 3H).

[0532] Step C: Compound 30-3 (1.8 g, 8.55 mmol) was dissolved in methanol (50 mL). Under argon protection, Raney nickel (200.00 mg, 2.33 mmol) was added to the reaction flask. The reaction mixture was purged three times with argon. The reaction mixture was reacted for 12 hours at hydrogen pressure (40 psi) and temperature (20-25 °C). The reaction mixture was filtered through diatomaceous earth, and the crude product was collected by vacuum concentration. The crude product was then passed through a rapid silica gel column chromatography column (eluting buffer: 0-10% methanol / dichloromethane) to give compound 30-4 (750 mg). MS (ESI) M / Z: 183.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.27 (br s, 1H), 7.86 (br d, J = 8.0Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 3.39 (dt, J = 2.8, 6.4Hz, 2H), 2.97 (br t, J = 6.4Hz, 2H).

[0533] Step D: Compound 30-4 (0.4 g, 2.19 mmol) was dissolved in dimethyl sulfoxide (10 mL). Cis-2,6-dimethylmorpholine (2.52 g, 21.91 mmol) was added to the reaction mixture. N,N-diisopropylethylamine (1.42 g, 10.95 mmol, 1.91 mL) and cesium fluoride (1.66 g, 10.95 mmol) were added separately to the reaction system. The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (25 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column (eluting with 0-10% methanol / dichloromethane) to give compound 30-5 (270 mg). MS(ESI)M / Z:262.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ = 7.39 (d, J = 8.5Hz, 1H), 7.29 (br s, 1H), 6.75 (d, J = 8.5Hz, 1H), 4.15 (br d,J=11.3Hz,2H),3.72(ddd,J=2.5,6.3,10.3Hz,2H),3.54(dt,J=2.9,6.6Hz,2 H), 2.89 (t, J = 6.5Hz, 2H), 2.56 (dd, J = 10.8, 12.3Hz, 2H), 1.27 (d, J = 6.3Hz, 6H).

[0534] Step E: Compound 30-5 (0.45 g, 1.72 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), purged three times with nitrogen, and a solution of lithium aluminum hydride (2.5 M, 1.38 mL) was slowly added dropwise to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 70 °C for 2 hours. After the reaction was complete, the temperature was lowered to 20-25 °C, and the reaction solution was quenched by adding water (20 mL) and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 30-6 (400 mg). MS (ESI) M / Z: 248.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ = 7.22 (br d, J = 8.5Hz, 1H), 6.46 (d, J = 8.5Hz, 1H), 4.01 (br d,J=12.3Hz,2H),3.97-3.87(m,2H),3.79-3.66(m,2H),3.10(t,J=5.8Hz, 2H), 2.67(t,J=5.6Hz,2H), 2.45(t,J=11.5Hz,2H), 1.28(d,J=5.6Hz,6H).

[0535] Step F: Compound 30-6 (0.4 g, 1.62 mmol) was dissolved in dimethyl sulfoxide (10 mL). 4-Fluoropyridine-2-carboxynitrile (592.39 mg, 4.85 mmol) and N,N-diisopropylethylamine (4.85 mmol, 845.08 μL) were added to the reaction mixture. The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (25 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-50% ethyl acetate / hexane) to give compound 30-7 (250 mg). MS (ESI) M / Z: 350.0 [M+H] + .

[0536] Step G: Compound 30-7 (0.1 g, 286.18 μmol) was dissolved in dichloromethane (10 mL), purged three times with nitrogen, and the reaction mixture was cooled to -78 °C. Diisobutylaluminum hydride solution (1 M, 715.45 μL) was added dropwise to the reaction system, and the reaction mixture was stirred at -78 °C for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (30 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 30-8 (110 mg). MS (ESI) M / Z: 354.3 [M+H] + .

[0537] Step H: Compound 30-8 (70.16 mg, 198.51 μmol) and compound 24-C (0.04 g, 132.34 μmol) were added to a pyridine (3 mL) solution, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.05 mg, 198.51 μmol). The reaction mixture was stirred at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative-grade HPLC (column type: 52-Welch Xtimate C18 150×30 mm, 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 55%-85%) to obtain compound 30 (9.5 mg). MS (ESI) M / Z: 638.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.41 (br d, J = 2.0Hz, 1H), 8.82 (s, 1H), 8.62 (s, 1H), 8.12 (s, 1H), 7.38 (br d,J=6.8Hz,1H),6.91(s,1H),6.82(s,1H),6.71(d,J=7.2Hz,1H),6.52-6.29(m,1H),4.84-4.66(m,1H),4.52(br d,J=1.8Hz,3H),4.34(br s,2H),4.07(br d,J=11.5Hz,2H),3.62(br s,4H),3.18-2.89(m,1H),2.83-2.67(m,3H),2.31(br t,J=10.8Hz,2H),1.15(d,J=4.0Hz,6H).

[0538] Example 31 Preparation of compounds 31A and 31B

[0539] Operating steps:

[0540] Step A: Compound 5-3 (692 mg, 3.06 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Then, 1,4-dibromobutane (727.78 mg, 3.37 mmol, 406.81 μL) and potassium carbonate (3.00 g, 9.19 mmol) were added sequentially to the above solution. The reaction mixture was then stirred at 25 °C for 12 hours. The reaction solution was quenched with water (30 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-100% ethyl acetate / n-hexane) to give 31-1 (315 mg). MS (ESI) M / Z: 281.2 [M+H] + .

[0541] Step B: Compound 31-1 (315 mg, 1.12 mmol) was dissolved in acetonitrile (3 mL) under nitrogen protection at 25 °C. Then, diethylaminosulfur trifluoride (90.57 mg, 561.86 μmol, 74.23 μL) and a selective fluorine reagent (398.09 mg, 1.12 mmol) were added to the above solution. The reaction mixture was then stirred at 25 °C for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 31-2 (335 mg). MS (ESI) M / Z: 299.1 [M+H] + .

[0542] Step C: Compound 31-2 (335 mg, 1.12 mmol) was dissolved in methanol (3.0 mL) and water (1.5 mL) at 25 °C. Subsequently, potassium persulfate complex (512.66 mg, 3.37 mmol) was added to the above solution. The reaction mixture was then stirred at 50 °C for 12 hours. The reaction mixture was quenched with an aqueous sodium sulfite solution (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0-25% ethyl acetate / n-hexane) to give 31-3 (100 mg). MS (ESI) M / Z: 331.0 [M+H] + .

[0543] Step D: Compound 31-3 (100 mg, 302.75 μmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL) at 25 °C. Then, sodium hydroxide (24.22 mg, 605.50 μmol) was added to the solution. The reaction mixture was then stirred at 25 °C for 1 hour. The solution was diluted with water (3 mL) and the pH was adjusted to 4 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL × 2). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by SFC (conditions: column type: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [carbon dioxide-methanol (0.1% ammonia)]; gradient: 35%) to obtain compound 31-4A (40mg) and compound 31-4B (30mg).

[0544] Compound 31-4A: SFC RT = 1.189 min; ee% = 99.74%; MS (ESI) M / Z: 317.1 [M+H] + .

[0545] Compound 31-4B: SFC RT = 1.425 min; ee% = 96.85%; MS (ESI) M / Z: 317.0 [M+H] + .

[0546] Step E: Compound 31-4A or 31-4B (40 mg, 126.47 μmol, parallel feed) and compound IE (53.41 mg, 126.47 μmol) were dissolved in pyridine (1.5 mL). Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (36.37 mg, 189.71 μmol) was added sequentially to the above solution. The reaction system was then stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: 57-Phenomenex Gemini NX C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 55%-85%) to obtain compounds 31A (35 mg) and 31B (25 mg), respectively.

[0547] Compound 31A: SFC RT = 1.503 min; ee% = 100%. MS (ESI) M / Z: 648.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)9.70(br t,J=5.52Hz,1H),9.40(s,1H),8.95(s,1H),8.73(s,1H),8.69-8.60(m,2H),7.94-7.83(m,2H),7.73(t,J=7.78Hz,1H),7.02(br d,J=8.28Hz,1H),6.26-6.06(m,1H),5.04-4.62(m,4H),4.31(br d,J=12.30Hz,2H), 3.72-3.61(m,2H), 2.53-2.52(m,1H), 2.47-2.43(m,1H), 2.26-1.85(m,4H), 1.21(br d,J=6.27Hz,6H). SFC (Column: Chiralpak AD-3 50×4.6mm ID,3um. Mobile phase: A: carbon dioxide B: ethanol (0.2% ammonia methanol); gradient: 50%) RT=1.503min; ee%=100%. Compound 31B: SFC RT=4.324min; ee%=96.51%. MS (ESI) M / Z:648.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)9.70(br t,J=5.77Hz,1H),9.40(s,1H),8.95(d,J=1.25Hz,1H),8.73(d,J=1.26Hz,1H),8.69-8.60(m,2H),7.93-7 .83(m,2H),7.74(t,J=8.03Hz,1H),7.02(d,J=8.53Hz,1H),6.26-6.06(m,1H),5.07-4.60(m,4H),4.31(br d,J=11.54Hz,2H),3.72-3.62(m,2H),2.53-2.52(m,1H),2.47-2.46(m,1H),2.25-1.87(m,4H),1.21(d,J=6.27Hz,6H).

[0548] Example 32 Preparation of compounds 32A and 32B

[0549] Operating steps:

[0550] Compound 23-5 hydrochloride (31 mg, 81.82 μmol) was added to a pyridine (2 mL) solution of compound 24-C (24.73 mg, 81.82 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.53 mg, 122.73 μmol). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was preparatively separated by HPLC (column type: 44-Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; gradient: 54%-84%) to give compound 32A (11.68 mg) and compound 32B (7.23 mg).

[0551] Compound 32A: HPLC RT = 3.962 min; MS (ESI) M / Z: 627.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.56(br t,J=5.65Hz,1H),8.84(d,J=1.00Hz,1H),8.68-8.57(m,2H),7.78-7.56(m,3H),7.14(d,J=7.53Hz,1H),6.95-6.78(m,2H),6.52-6.27(m,1H ),4.87-4.48(m,4H),4.31-4.06(m,2H),3.67-3.54(m,2H),3.15-2.89 (m,1H),2.79-2.67(m,1H),2.44-2.36(m,2H),1.16(d,J=6.02Hz,6H).

[0552] Compound 32B: HPLC RT = 4.202 min; MS (ESI) M / Z: 627.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.56-9.38(m,1H),8.78-8.69(m,1H),8.64-8.52(m,2H),7.44-7.31(m,3H),6.74-6.57(m,2H),6.52-6.30(m ,2H),4.83-4.48(m,4H),3.46-3.35(m,4H),3.15-2.97(m,1H),2.81-2.68(m,1H),2.06-1.94(m,2H),0.98(br d,J=5.77Hz,6H).

[0553] Example 33 Preparation of compound 33

[0554] Operating steps:

[0555] Step A: Sodium hydride (119.00 mg, 2.98 mmol, 60%) was added to a tetrahydrofuran (10 mL) solution of compound 33-1 (500 mg, 2.38 mmol). The mixture was stirred at 0 °C for 5 minutes. Then, compound 1a (275.68 mg, 1.98 mmol, 186.40 μL) was added to the mixture. The mixture was stirred at 50 °C for 2 hours. The reaction mixture was quenched with 15 mL of water at 20 °C, followed by extraction with ethyl acetate (15 mL × 3). The organic phase was separated, and the combined organic layers were washed with saturated sodium bicarbonate solution (15 mL × 1) and saturated brine (15 mL × 1), respectively. The layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-2 (270 mg), which was used directly in the next step. MS (ESI) M / Z: 268.0 [M+H] + .

[0556] Step B: To a solution (3 mL) of compound 33-2 (220 mg, 820.44 μmol), pinacol diborate (250.01 mg, 984.53 μmol), and a dioxane solution (3 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (90.05 mg, 123.07 μmol), potassium acetate (241.56 mg, 2.46 mmol) were added, and nitrogen was introduced to replace the nitrogen atmosphere. The mixture was then stirred at 90 °C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography (0–10% ethyl acetate / petroleum ether) to obtain compound 33-3 (250 mg). MS (ESI) M / Z: 316.1 [M+H] + .

[0557] Step C: To a mixed solution of compound IC (246.02 mg, 837.53 μmol), compound 33-3 (240 mg, 761.39 μmol), dioxane (6 mL), and water (1.5 mL), palladium dichloride dichloride (53.44 mg, 76.14 μmol), sodium carbonate (161.40 mg, 1.52 mmol), and nitrogen purging were added, and the mixture was stirred at 90 °C under nitrogen protection for 2 hours. The reaction mixture was quenched with water (10 mL) at 20 °C, followed by extraction with ethyl acetate (10 mL × 3). The organic phase was separated, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–63% ethyl acetate / petroleum ether) to obtain compound 33-4 (280 mg). MS (ESI) M / Z: 447.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.32 (s, 1H), 8.58 (d, J = 8.7Hz, 1H), 8.21 (d, J = 8.7Hz, 1H) ,7.76-7.70(m,2H),7.64-7.58(m,2H),7.24(t,J=7.7Hz,1H),7.01(s,1H),4.44(br d,J=6.0Hz,2H),4.38(t,J=5.4Hz,2H),3.64(t,J=5.2Hz,2H),3.33(s,3H),3.21(s,3H),1.46(s,9H).

[0558] Step D: Add compound 33-4 (60 mg, 134.37 μmol) to a hydrochloric acid / dioxane solution (2 M, 1.5 mL). Stir the solution at 20 °C for 0.5 h. Concentrate the reaction mixture under reduced pressure to remove the hydrochloric acid / dioxane, giving compound 33-5 hydrochloride (40 mg), which can be used directly in the next step. MS (ESI) M / Z: 347.0 [M+H] + .

[0559] Step E: To a pyridine (0.5 mL) solution of compound 24-C (28.71 mg, 94.97 μmol) and compound 33-5 hydrochloride (40 mg, 104.47 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.31 mg, 142.46 μmol) was added. The solution was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove pyridine. The crude product was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 45%-75%) to give compound 33 (21.21 mg). MS (ESI) M / Z: 631.1 [M+H] + . 1 H NMR (400MHz, MeOH-d4) δ = 9.29 (br s, 1H), 8.72 (br d, J = 3.7Hz, 2H), 8.55 (br d, J = 8.7Hz, 1H), 8.14 (br d,J=8.5Hz,1H),7.99(s,1H),7.59(d,J=7.4Hz,1H),7.52(d,J=8.0Hz,1H), 7.25(t,J=7.7Hz,1H),6.75(s,1H),6.09-5.93(m,1H),4.95(s,2H),4.92(br s,1H),4.61-4.54(m,1H),4.37(t,J=5.3Hz,2H),3.69(t,J=5.4Hz,2H),3.25(s,3H),3.14-3.00(m,1H),2.72-2.61(m,1H),2.48(s,3H). 19 F NMR(376MHz,DMSO-d6)-133.63(s,1F),-174.65(s,1F).

[0560] Example 34 Preparation of compound 34

[0561] Operating steps:

[0562] Step A: 2-Bromo-6-fluoropyridine (500 mg, 2.84 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 3.69 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, followed by the addition of cesium carbonate (2.78 g, 8.52 mmol). The mixture was then stirred at 80 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the mixture. After standing and separation, the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 34-1 (456 mg). MS (ESI) M / Z: 271.1 [M + H + 2] + .

[0563] Step B: Compound 34-1 (100 mg, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (0.086 g, 0.074 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Hexa-n-butylditin (0.26 g, 0.44 mmol) was then added, and the system was purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL), and the organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 34-2 (230 mg). MS (ESI) M / Z: 481.2 [M+H] + .

[0564] Step C: Compound IC (100 mg, 0.34 mmol) and compound 34-2 (0.16 g, 0.34 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Then, palladium dichloride (0.048 g, 0.068 mmol) was added. The system was then purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL). The organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 34-3 (113 mg) was purified by column chromatography. MS (ESI) M / Z: 448.3 [M+H] + .

[0565] Step D: Compound 34-3 (30 mg, 0.067 mmol) was dissolved in ethyl acetate (1 mL) at room temperature, followed by the addition of ethyl acetate hydrochloride solution (1 mL). The mixture was then stirred at room temperature for 1 hour. The system was concentrated to obtain the crude product, yielding compound 34-4 hydrochloride (30 mg). MS (ESI) M / Z: 348.3 [M+H] + .

[0566] Step E: Compound 24-C (20 mg, 0.066 mmol) and compound 34-4 (25.3 mg, 0.066 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. Then, N,N-diisopropylethylamine (26 mg, 0.20 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (30 mg, 0.099 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 34 (7 mg) was prepared by reverse phase reaction. MS (ESI) M / Z: 632.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.70(t,J=5.8Hz,1H),9.40(s,1H),8.90(s,1H),8.71-8.59(m ,3H),7.93-7.83(m,2H),7.72(t,J=7.9Hz,1H),6.90(d,J=8.5Hz,1H),6.40(dt,J=45. 3,5.7Hz,1H),4.86(d,J=5.7Hz,2H),4.77(ddd,J=14.9,9.0,2.5Hz,1H),4.62-4.46(m ,3H),4.00(d,J=12.2Hz,2H),3.13-2.97(m,3H),2.78-2.64(m,1H),1.93-1.73(m,4H).

[0567] Example 35 Preparation of compound 35

[0568] Operating steps:

[0569] Step A: 2-oxa-6-azaspiro[3.4]octane (200 mg, 1.77 mmol) and 2-bromo-6-fluoropyridine (311.50 mg, 1.77 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, followed by the addition of cesium carbonate (1.73 g, 5.31 mmol). The mixture was then stirred at 80 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the mixture. After standing and separating the layers, the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 35-1 (300 mg). MS (ESI) M / Z: 271.1 [M + H + 2] + .

[0570] Step B: Compound 35-1 (100 mg, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Hexa-n-butylditin (0.26 g, 0.44 mmol) was then added, and the system was purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL), and the organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 35-2 (200 mg). MS (ESI) M / Z: 481.2 [M+H] + .

[0571] Step C: Compound IC (100 mg, 0.34 mmol) and compound 35-2 (0.16 g, 0.34 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Then, palladium dichloride (48 mg, 0.068 mmol) was added. The system was then purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL). The organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 35-3 (100 mg) was purified by column chromatography. MS (ESI) M / Z: 448.2 [M+H] + .

[0572] Step D: Compound 35-3 (30 mg, 0.067 mmol) was dissolved in dichloromethane (2 mL) at room temperature, followed by the dropwise addition of trifluoroacetic acid (0.2 mL). The system was then stirred at room temperature for 1 hour. The system was concentrated to obtain compound 35-4 trifluoroacetate (32 mg). MS (ESI) M / Z: 348.3 [M+H] + .

[0573] Step E: Compound 24-C (20 mg, 0.066 mmol) and trifluoroacetate of compound 35-4 (29.3 mg, 0.066 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. Then, N,N-diisopropylethylamine (26 mg, 0.20 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (30 mg, 0.099 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 35 (7 mg) was prepared by reverse phase resection. MS (ESI) M / Z: 632.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.70(t,J=5.8Hz,1H),9.40(s,1H),8.90(d,J=1.5Hz,1H),8.6 8(d,J=6.0Hz,3H),7.88-7.79(m,2H),7.68(t,J=7.9Hz,1H),6.63(d,J=8.3Hz,1H),6. 40(dt,J=45.3,5.8Hz,1H),4.86(d,J=5.7Hz,2H),4.77(ddd,J=15.0,9.0,2.5Hz,1H), 4.64(d,J=6.0Hz,2H),4.56(d,J=6.1Hz,2H),3.81(s,2H),3.53(t,J=6.9Hz,2H),3.09 -2.99(m,1H),2.76–2.69(m,1H),2.30(t,J=7.0Hz,2H),1.97(t,J=6.2Hz,1H).

[0574] Example 36 Preparation of Compound 36

[0575] Operating steps:

[0576] Step A: (3S,4S)-3-fluoro-4-methoxypyrrolidine (300 mg, 2.52 mmol) and 2-bromo-6-fluoropyridine (443.49 mg, 2.52 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, followed by the addition of cesium carbonate (2.46 g, 7.56 mmol). The mixture was then stirred at 80 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the mixture. After standing and separation, the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 36-1 (148 mg). MS (ESI) M / Z: 277.0 [M + H + 2] + .

[0577] Step B: Compound 36-1 (148 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Hexa-n-butylditin (0.38 g, 0.65 mmol) was then added, and the system was purged with nitrogen and stirred at 110 °C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL), and the organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 36-2 (220 mg). MS (ESI) M / Z: 487.2 [M+H] + .

[0578] Step C: Compound IC (100 mg, 0.34 mmol) and compound 36-2 (0.16 g, 0.34 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature. Tetra(triphenylphosphine)palladium (79 mg, 0.068 mmol) was then added. The system was purged with nitrogen and stirred at 110°C for 5 hours. Water (10 mL) and ethyl acetate (10 mL × 2) were added to the system. After standing and separating the layers, the aqueous phase was quenched with saturated potassium fluoride solution (10 mL). The organic phase was washed with saturated brine (10 mL × 2) and saturated potassium fluoride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 36-3 (130 mg) was purified by column chromatography. MS (ESI) M / Z: 454.3 [M+H] + .

[0579] Step D: Compound 36-3 (30 mg, 0.066 mmol) was dissolved in ethyl acetate (1 mL) at room temperature, and ethyl acetate hydrochloride (4 M, 1 mL) was added dropwise. The system was then stirred at room temperature for 1 hour. The system was concentrated to give compound 36-4 hydrochloride (26 mg). MS (ESI) M / Z: 354.2 [M+H] + .

[0580] Step E: Compound 24-C (20 mg, 0.066 mmol) and compound 36-4 (0.026 g, 0.066 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. Then, N,N-diisopropylethylamine (0.026 g, 0.20 mmol) and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one (0.030 g, 0.099 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The crude product was directly concentrated, and then compound 36 (8 mg) was prepared by reverse phase resection. MS (ESI) M / Z: 638.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.71(t,J=5.8Hz,1H),9.40(s,1H),8.91(s,1H),8.68(d,J=5.9Hz,3H),7.86(d ,J=6.2Hz,2H),7.72(t,J=7.9Hz,1H),6.70(d,J=8.3Hz,1H),6.40(dt,J=45.3,5.8Hz,1H),5.38(dd,J= 49.7,3.3Hz,1H),4.86(d,J=5.8Hz,2H),4.77(ddd,J=15.0,9.0,2.4Hz,1H),4.56(ddd,J=15.0,8.5,2. 6Hz,1H),4.19(d,J=10.6Hz,1H),3.94-3.67(m,4H),3.40(s,3H),3.12-2.96(m,1H),2.80-2.63(m,1H).

[0581] Example 37 Preparation of compounds 37A and 37B

[0582] Operating steps:

[0583] Step A: A solution of compound 37-1 (200 mg, 781.08 μmol), 4-methoxybenzyl mercaptan (132.51 mg, 859.19 μmol, 119.70 μL), tris(dibenzylacetone)dipalladium (71.52 mg, 78.11 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (90.39 mg, 156.22 μmol), and N,N-diisopropylethylamine (403.79 mg, 3.12 mmol, 544.20 μL) in dioxane (4 mL) was purged three times with nitrogen. The mixture was then stirred at 100 °C under nitrogen for 12 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–70% ethyl acetate / n-hexane eluent) to obtain compound 37-2 (250 mg). MS(ESI)M / Z:330.1[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.60(d,J=0.95Hz,1H),8.14(d,J=0.95Hz,1H),7.12(d,J=8.58Hz,2H),6.77(d,J=8.70Hz,2H),4.23(s,2H),3.99(s,3H),3.77(s,3H).

[0584] Step B: The mixture of compound 37-2 (250 mg, 759.02 μmol) and trifluoroacetic acid (6 mL) was stirred at 80 °C for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain crude compound 37-3 (320 mg), which was directly used in the next step MS (ESI) M / Z: 210.0 [M+H). + .

[0585] Step C: Anhydrous potassium carbonate (845.52 mg, 6.12 mmol) was added to a solution of compound 37-3 (320 mg, 1.53 mmol), 1,3-dibromopropane (370.53 mg, 1.84 mmol, 187.14 μL), and N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered to remove the solids, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate / n-hexane eluent) to obtain compound 37-4 (100 mg). MS (ESI) M / Z: 249.9 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 8.56(d,J=1.26Hz,1H),8.06(d,J=1.00Hz,1H),5.11-4.99(m,2H),3.97(s,3H),3.33-3.24(m,2H),2.64(br t,J=6.15Hz,2H).

[0586] Step D: Under nitrogen protection and at 20°C, diethylaminosulfur trifluoride (32.33 mg, 200.57 μmol, 26.50 μL) was slowly added dropwise to a mixed solution of compound 37-4 (100 mg, 401.14 μmol) in acetonitrile (4 mL) and anhydrous dichloromethane (2 mL). Then, under anhydrous and oxygen-free conditions, the mixture was slowly added dropwise to a flask containing a selective fluorine reagent (170.53 mg, 481.37 μmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction was quenched by pouring the mixture into a saturated aqueous solution of sodium bicarbonate (40 mL), followed by extraction with ethyl acetate (90 mL × 3). The combined organic layers were washed with saturated brine (90 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 37-5 (160 mg). MS (ESI) M / Z: 268.0 [M+H] + .

[0587] Step E: Add potassium persulfate complex salt (1.10 g, 1.80 mmol) to a mixed solution of compound 37-5 (160 mg, 598.63 μmol) in methanol (5 mL) and water (5 mL). Stir the reaction solution at 20 °C for 48 hours. Dilute the reaction solution with water (20 mL), then extract with dichloromethane (40 mL × 2), dry with anhydrous sodium sulfate, combine the organic layers, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by rapid silica gel chromatography (0–30% ethyl acetate / n-hexane eluent) to obtain compound 37-6 (64 mg). MS (ESI) M / Z: 300.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.09(d,J=1.25Hz,1H),8.88(d,J=1.00Hz,1H),5.89-5.69(m,1H),5.36(ddd,J=14.87,9.72,2.76 Hz,1H),5.12(ddd,J=15.00,7.47,3.39Hz,1H),4.05(s,3H),3.32-3.10(m,1H),2.89-2.71(m,1H).

[0588] Step F: Lithium hydroxide monohydrate (53.84 mg, 1.28 mmol) was added to a tetrahydrofuran (2 mL) and water (0.5 mL) solution of compound 37-6 (64 mg, 213.85 μmol). The reaction solution was stirred at 20 °C for 2 hours. The reaction solution was diluted with water (10 mL), and the pH was adjusted to 2 with 2 M dilute hydrochloric acid. Extraction was then performed with ethyl acetate (40 mL × 2), the organic layers were dried over anhydrous sodium sulfate, combined, filtered, and concentrated under reduced pressure to obtain compound 37-7 (60 mg). MS (ESI) M / Z: 286.1 [M+H] + .

[0589] Step G: To a pyridine (2 mL) solution of compound 37-7 (60 mg, 210.34 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.48 mg, 315.51 μmol) and compound IE (81.17 mg, 210.34 μmol) were added. The mixture was stirred at 50 °C for 1.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column type: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 52%-82%) and lyophilized to obtain a racemic compound (46 mg). The racemate was subjected to chiral separation (column type: DAICL CHIRALPAK IE (250 mm * 30 mm, 10 μm); mobile phase: [n-heptane-acetonitrile:isopropanol = 1:2 (0.1% ammonia)]; B%: 60%) to give compound 37A (19.04 mg, Rf = 4.694 min) and compound 37B (17.91 mg, Rf = 5.729 min).

[0590] Compound 37A: SFC: Rf = 4.694 min; ee% = 100%; MS (ESI) M / Z: 617.1 [M+H] + . 11H NMR (400 MHz, CDCl3) δ ppm 9.27 (s, 1H), 8.96 (d, J = 0.83 Hz, 1H), 8.74 (d, J = 0.95 Hz, 1H), 8.65 (d, J = 8.58 Hz, 1H), 8.38 (d, J = 8.58 Hz, 1H), 8.04 (d, J = 7.39 Hz, 1H), 8.01 (s, 1H), 7.85 (br t, J = 4.23 Hz, 1H), 7.71 (t, J = 7.99 Hz, 1H), 6.79 (d, J = 8.34 Hz, 1H), 5.88 - 5.67 (m, 1H), 5.35 (ddd, J = 14.78, 9.54, 2.86 Hz, 1H), 5.11 (ddd, J = 14.87, 7.54, 3.34 Hz, 1H), 5.04 (d, J = 4.89 Hz, 2H), 4.16 - 4.28 (m, 2H), 3.86 - 3.75 (m, 2H), 3.30 - 3.13 (m, 1H), 2.89 - 2.72 (m, 1H), 2.64 (dd, J = 12.46, 10.79 Hz, 2H), 1.34 (d, J = 6.20 Hz, 6H). 19 19F NMR (376 MHz, CDCl3) -171.55 (s, 1F).

[0591] Compound 37B: SFC: Rf = 5.729 min; ee% = 99.15%; MS (ESI) M / Z: 617.1 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ ppm 9.27 (s, 1H), 8.95 (s, 1H), 8.74 (s, 1H), 8.65 (d, J = 8.58 Hz, 1H), 8.38 (d, J = 8.58 Hz, 1H), 8.04 (d, J = 7.51 Hz, 1H), 8.01 (s, 1H), 7.87 (br s, 1H), 7.71 (t, J = 7.93 Hz, 1H), 6.79 (d, J = 8.46 Hz, 1H), 5.88 - 5.66 (m, 1H), 5.35 (ddd, J = 14.66, 9.54, 2.74 Hz, 1H), 5.11 (ddd, J = 14.81, 7.60, 3.22 Hz, 1H), 5.04 (br d, J = 4.77 Hz, 2H), 4.22 (br d, J = 11.92 Hz, 2H), 3.87 - 3.74 (m, 2H), 3.31 - 3.10 (m, 1H), 2.89 - 2.72 (m, 1H), 2.64 (t, J = 11.56 Hz, 2H), 1.34 (d, J = 6.20 Hz, 6H). 19F NMR(376MHz, CDCl3)-171.57(s,1F).

[0592] Example 38 Preparation of compounds 38A, 38B, 38C and 38D

[0593] Operating steps:

[0594] Step A: At room temperature, 2-mercaptoethanol-1-ol (8.20 g, 104.95 mmol, 7.35 mL) was added to a solution of compound 38-1 (20 g, 87.32 mmol), potassium carbonate (36.20 g, 261.96 mmol), and N,N-dimethylformamide (400 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (0-60% ethyl acetate / n-hexane eluent) to give compound 38-2 (9.9 g). MS (ESI) M / Z: 288.9 [M+2+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 7.49 (d, J = 1.07Hz, 1H), 7.38 (s, 1H), 5.08 (t, J = 5.54Hz, 1H), 3.71-3.60 (m, 2H), 3.13-3.02 (m, 4H), 2.62-2.57 (m, 2H).

[0595] Step B: Under ice bath conditions, lithium borohydride (2M, 51.71mL) was slowly added dropwise to a mixed solution of compound 38-2 (9.9g, 34.47mmol) in tetrahydrofuran (180mL) and ethanol (18mL). The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (150mL) and extracted with ethyl acetate (200mL × 2). The organic phase was washed with saturated brine (200mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (0-5% methanol / dichloromethane eluent) to give compound 38-3 (7.3g). MS (ESI) M / Z: 273.1 [M-18+H] + . 1H NMR(400MHz,DMSO-d6)δppm 7.29(s,1H),7.23(s,1H),5.15-4.79(m,3H),3.57(q,J=6.36Hz,2H),3.15–2.97(m ,3H),2.71(ddd,J=16.25,8.72,2.89Hz,1H),2.27-2.10(m,1H),1.94-1.79(m,1H).

[0596] Step C: Under a nitrogen atmosphere, tributyl cyanomethylene phosphate (6.68 g, 27.66 mmol) was added to a toluene (80 mL) solution of compound 38-3 (4 g, 13.83 mmol). The reaction mixture was stirred at 110 °C for 0.5 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (0-4% ethyl acetate / n-hexane eluent) to give compound 38-4 (520 mg). MS (ESI) M / Z: 271.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 7.38(s,1H),7.31(s,1H),5.08(dd,J=7.87,6.68Hz,1H),4.35-4.21(m,1H),3.84(ddd,J=12.46,9.00,1.67Hz,1 H),3.09(ddd,J=14.90,5.19,1.61Hz,1H),3.04-2.85(m,3H),2.77(dt,J=16.66,8.42Hz,1H),1.95-1.66(m,1H).

[0597] Step D: Under a nitrogen atmosphere, 1,1-bis(diphenylphosphine)ferrocene palladium(II) dichloromethane complex (78.30 mg, 95.88 μmol) was added to a methanol (10 mL) solution of compound 38-4 (520 mg, 1.92 mmol) and triethylamine (388.08 mg, 3.84 mmol, 533.81 μL). The reaction mixture was stirred at 80 °C for 12 hours under a carbon monoxide atmosphere (15 psi). The reaction mixture was then concentrated directly under reduced pressure. The crude product was purified by rapid silica gel column chromatography (0-12% ethyl acetate / n-hexane eluent) to give compound 38-5 (410 mg). MS (ESI) M / Z: 251.1 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 7.97 (s, 1H), 7.74 (s, 1H), 5.17 (br t, J = 7.03Hz, 1H), 4.45 (br d, J = 12.80Hz, 1H), 3.98 (br t,J=11.17Hz,1H),3.91(s,3H),3.20-3.09(m,1H),3.08-2.97(m,1H),2.92-2.79(m,2H),2.70-2.55(m,1H),2.08(dq,J=15.00,7.30Hz,1H).

[0598] Step E: Under a nitrogen atmosphere, diethylaminosulfur trifluoride (96.59 mg, 599.25 μmol, 79.17 μL) was added dropwise to a mixed solution of compound 38-5 (300 mg, 1.20 mmol) in dichloromethane (3 mL) and acetonitrile (6 mL). After stirring the reaction solution at room temperature for 0.5 hours, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (509.50 mg, 1.44 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated sodium carbonate aqueous solution (15 mL) and extracted twice with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 38-6 (170 mg). MS (ESI) M / Z: 269.2 [M+H] + .

[0599] Step F: Potassium persulfate complex (460.44 mg, 3.33 mmol) was added to a mixed solution of compound 38-6 (170 mg, 633.61 μmol) in methanol (6 mL) and water (6 mL). The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by rapid silica gel column chromatography (0-20% ethyl acetate / n-hexane eluent), followed by preparative separation by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [carbon dioxide-ethanol (0.1% ammonia O)]; gradient: 45%) to obtain compounds 38-7A (20 mg), 38-7B (50 mg), 38-7C (20 mg), and 38-7D (45 mg).

[0600] Compound 38-7A: SFC RT = 0.870 min; ee% = 100%; MS (ESI) M / Z: 301.2 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 8.58(s,1H),8.23(s,1H),5.52(dd,J=8.53,5.27Hz,1H),5.39-5.18(m,1H),4. 57-4.44(m,2H),3.97(s,3H),3.24(ddd,J=16.69,10.16,4.02Hz,1H),2.99(br d,J=7.03Hz,1H),2.77(br dd,J=9.41,4.39Hz,1H),2.24(br d,J=6.78Hz,1H).

[0601] Compound 38-7B: SFC RT = 0.952 min; ee% = 98.92%; MS (ESI) M / Z: 301.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.59(s,1H),8.22(s,1H),5.40(dd,J=8.28,5.52Hz,1H),5.33-5.14(m,1H),4.48-4.37(m,2H),3.9 8(s,3H),3.25-3.13(m,1H),2.98(dt,J=16.69,8.22Hz,1H),2.83-2.71(m,1H),2.25-2.02(m,1H).

[0602] Compound 38-7C: SFC RT = 1.021 min; ee% = 98.46%; MS (ESI) M / Z: 301.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.58(s,1H),8.23(s,1H),5.52(dd,J=8.53,5.02Hz,1H),5.43-5.16(m,1H),4.58-4.45(m,2H),3.97(s ,3H),3.24(ddd,J=16.50,9.98,4.14Hz,1H),3.06-2.91(m,1H),2.86-2.70(m,1H),2.34-2.13(m,1H).

[0603] Compound 38-7D: SFC RT = 1.448 min; ee% = 99.9%; MS (ESI) M / Z: 301.2 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 8.59(s,1H),8.22(s,1H),5.40(dd,J=8.28,5.52Hz,1H),5.32-5.05(m,1H),4.47-4.38(m,2 H),3.98(s,3H),3.26-3.11(m,1H),3.04-2.91(m,1H),2.84-2.69(m,1H),2.24-2.10(m,1H).

[0604] Step G: Lithium hydroxide monohydrate (16.77 mg, 399.60 μmol) was added to a mixed solution of compound 38-7A (20 mg, 66.60 μmol) in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (5 mL), the pH was adjusted to 1-2 with 4 M hydrochloric acid, and then extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 38-8A (20 mg) was obtained without purification. MS (ESI) M / Z: 287.1 [M+H] + .

[0605] Compounds 38-7B (40 mg), 38-7C (20 mg), and 38-7D (45 mg) were fed in parallel under the same conditions to obtain compound 38-8B (38 mg), MS (ESI) M / Z: 287.0 [M+H]. + ; 38-8C (20mg), MS (ESI) M / Z: 287.0 [M+H]+; 38-8D (40mg), MS (ESI) M / Z: 287.0 [M+H]+.

[0606] Step H: To a pyridine (1 mL) solution of compound 38-8A (20 mg, 69.86 μmol) and compound IE (32.46 mg, 76.85 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.17 mg, 199.11 μmol, 1.5 eq) was added, and the reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated and evaporated to dryness, and then preparatively separated by HPLC (column type: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 46%-76%) to obtain compound 38A (18.41 mg).

[0607] Compounds 38-8B (38 mg), 38-8C (20 mg), and 38-8D (40 mg) were fed in parallel under the same conditions to obtain compounds 38B (43.78 mg), 38C (19.16 mg), and 38D (41.38 mg), respectively.

[0608] Compound 38A: MS (ESI) M / Z: 618.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.29(s,1H),8.68(d,J=8.53Hz,1H),8.40(d,J=8.78Hz,1H),8.36(s,1H),8.17(s,1H),8.08-7.99(m,2H),7.80-7.66(m,2H), 6.80(d,J=8.53Hz,1H),5.52(dd,J=8.28,5.02Hz,1H),5.40-5.21(m,1H),5.01(d,J=5.02Hz,2H),4.66-4.47(m,2H),4.23(br d,J=12.05Hz,2H),3.87-3.74(m,2H),3.31-3.17(m,1H),3.06-2.91(m,1H),2.78(ddt,J=14.09,9. 25,4.52,4.52Hz,1H),2.64(dd,J=12.17,10.92Hz,2H),2.28-2.18(m,1H),1.34(d,J=6.27Hz,6H).

[0609] Compound 38B: MS (ESI) M / Z: 618.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (broad t, J = 5.65 Hz, 1H), 9.40 (singlet, 1H), 8.70 - 8.56 (multiplet, 2H), 8.43 (singlet, 1H), 8.28 (singlet, 1H), 7.90 (doublet, J = 7.28 Hz, 1H), 7.81 (singlet, 1H), 7.74 (triplet, J = 7.91 Hz, 1H), 7.03 (doublet, J = 8.78 Hz, 1H), 6.17 - 5.86 (multiplet, 1H), 5.48 - 5.27 (multiplet, 1H), 4.82 (broad doublet, J = 5.77 Hz, 2H), 4.56 - 4.41 (multiplet, 1H), 4.37 - 4.22 (multiplet, 3H), 3.73 - 3.61 (multiplet, 1H), 3.78 - 3.58 (multiplet, 1H), 3.24 (broad singlet, 3H), 2.78 - 2.60 (multiplet, 1H), 2.47 (broad singlet, 1H), 2.08 - 1.92 (multiplet, 1H), 1.21 (doublet, J = 6.02 Hz, 6H).

[0610] Compound 38C: MS (ESI) M / Z: 618.1 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ ppm 9.27 (singlet, 1H), 8.66 (doublet, J = 8.78 Hz, 1H), 8.38 (doublet, J = 8.53 Hz, 1H), 8.35 (singlet, 1H), 8.17 (singlet, 1H), 8.05 (doublet, J = 7.53 Hz, 1H), 8.01 (singlet, 1H), 7.72 (triplet, J = 7.91 Hz, 1H), 7.68 - 7.62 (multiplet, 1H), 6.79 (doublet, J = 8.53 Hz, 1H), 5.52 (doublet of doublets, J = 8.53, 5.02 Hz, 1H), 5.40 - 5.22 (multiplet, 1H), 5.00 (broad doublet, J = 5.02 Hz, 2H), 4.65 - 4.46 (multiplet, 2H), 4.23 (broad doublet, J = 11.29 Hz, 2H), 3.81 (triplet of doublets of doublets, J = 10.16, 6.40, 2.26 Hz, 2H), 3.31 - 3.18 (multiplet, 1H), 3.07 - 2.93 (multiplet, 1H), 2.84 - 2.71 (multiplet, 1H), 2.64 (doublet of doublets, J = 12.30, 10.79 Hz, 2H), 2.31 - 2.17 (multiplet, 1H), 1.34 (doublet, J = 6.02 Hz, 6H).

[0611] Compound 38D: MS (ESI) MS(ESI) M / Z: 618.4 [M + H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.71-9.54(m,1H),9.40(s,1H),8.73-8.60(m,2H),8.43(s,1H),8.28(s,1H),7.90(d,J=7.2 8Hz,1H),7.81(s,1H),7.78-7.71(m,1H),7.03(d,J=8.53Hz,1H),6.15-5.91(m,1H),5.39(br t,J=6.90Hz,1H),4.82(br d,J=5.02Hz,2H),4.56-4.40(m,1H),4.37-4.22(m,3H),3.73-3.62(m,2H),3.23-2.86(m,3H),2.78-2.59(m,1H),2.47(br s,1H),2.07-1.97(m,1H),1.21(d,J=6.02Hz,6H).

[0612] Example 39 Preparation of compound 39

[0613] Operating steps:

[0614] Step A: To a mixed solution of compound 39-1 (500 mg, 2.33 mmol) in toluene (5 mL) and water (1 mL), potassium cyclopropanetrifluoroborate (690 mg, 4.66 mmol, CAS: 1065010-87-8), palladium acetate (26 mg, 115.81 μmol), potassium phosphate (990 mg, 4.66 mmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (109 mg, 233.59 μmol) were added to degas the mixture, purging three times with nitrogen. The mixture was then stirred at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (elution buffer: 0-70% ethyl acetate / hexane gradient) to give compound 39-2 (405 mg). MS (ESI) M / Z: 177.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.54 (d, J=1.6Hz, 1H), 6.65 (d, J=1.6Hz, 1H), 4.82 (br s,1H),4.25-4.15(m,2H),3.56-3.47(m,2H),1.81-1.72(m,1H),0.93-0.80(m,2H),0.63-0.50(m,2H).

[0615] Step B: Compound 39-2 (65 mg, 368.87 μmol), tris(dibenzylacetone)dipalladium (30 mg, 32.76 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (40 mg, 69.13 μmol), and cesium carbonate (280 mg, 859.37 μmol) were added to 1 mL of dioxane (100 mg, 340.43 μmol) for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (elution buffer: 0-60% ethyl acetate / hexane gradient) to give compound 39-3 (130 mg). MS(ESI)M / Z:434.2[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.97 (s, 1H), 8.34 (d, J = 9.2Hz, 1H), 8.02 (d, J = 9.2Hz, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.59 (s, 1H), 6.88 (d, J = 1.6Hz, 1H), 5.49 (br d,J=1.2Hz,1H),4.59(br d,J=4.8Hz,2H),4.52-4.44(m,2H),4.41-4.33(m,2H),1.94-1.84(m,1H),1.49(s,9H),1.04-0.98(m,2H),0.73-0.67(m,2H).

[0616] Step C: To a solution of compound 39-3 (130 mg, 299.88 μmol) in dichloromethane (1 mL), add 2 M hydrochloric acid / dioxane solution (1.5 mL) and stir the mixture at 20 °C for 2 hours. Concentrate the reaction mixture under reduced pressure to give compound 39-4 hydrochloride (120 mg). MS (ESI) M / Z: 334.1 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.49(s,1H),8.82(d,J=9.6Hz,1H),8.47(s,1H),8.26(d,J=1.6Hz,1H),8.02(d,J=9.6Hz,1H),7.62(d,J=1 .6Hz,1H),4.63-4.57(m,4H),4.53-4.48(m,2H),2.17-2.07(m,1H),1.21-1.15(m,2H),0.92-0.87(m,2H).

[0617] Step D: To a pyridine (0.5 mL) solution of compound 39-4 hydrochloride (45 mg, 121.67 μmol), 24-C (25 mg, 82.71 μmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 166.93 μmol) were added. The mixture was stirred at 50 °C for 1 hour. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; gradient: 33%-63%) to give compound 39 (18.3 mg).

[0618] MS(ESI)M / Z:618.1[M+H] + . 1 H NMR (400MHz, MeOH-d4) δppm 9.50 (s, 1H), 8.77 (s, 1H), 8.69 (d, J = 1.2Hz, 1H), 8.67 (br d,J=9.6Hz,1H),8.39-8.28(m,2H),8.04(d,J=1.6Hz,1H),7.43(br s,1H),6.13-5.95(m,1H),5.02(s,2H),4.94(br d,J=3.6Hz,1H),4.62-4.55(m,1H),4.53(s,4H),3.15-3.04(m,1H),2.7 0-2.63(m,1H),2.10-2.00(m,1H),1.16-1.09(m,2H),0.86-0.79(m,2H).

[0619] Example 40: Preparation of Compound 40 (Russian)

[0620] Operating steps:

[0621] Step A: A solution of compound 40-1 (10 g, 33.91 mmol), compound trimethylsilylacetylene (5.17 mL, 37.30 mmol), palladium dichloride bis(triphenylphosphine) (2.38 g, 3.39 mmol), cuprous iodide (1.29 g, 6.78 mmol), and triethylamine (14.16 mL, 101.72 mmol) in tetrahydrofuran (200 mL) was purged three times with nitrogen, and then stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–10% ethyl acetate / n-hexane eluent gradient) to obtain compound 40-2 (8.14 g). MS (ESI) M / Z: 312.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.07 (d, J = 1.76Hz, 1H), 8.49 (d, J = 1.76Hz, 1H), 3.97 (s, 3H), 0.32 (s, 9H).

[0622] Step B: Trifluoroacetic acid (13.04 mL, 175.59 mmol) was added dropwise to a mixed solution of compound O-trimethylbenzenesulfonyl ethoxyoxime ethyl ester (2.93 g, 10.28 mmol) in dichloromethane (3 mL) and water (4 mL) at 0 °C. The mixture was then stirred at 0 °C for 2 hours and at 20 °C for 1 hour. Then, a solution of compound 40-2 (1.5 g, 4.80 mmol) in dichloromethane (3 mL) was added dropwise to this reaction solution at 20 °C, and the reaction solution was stirred at 20 °C for 12 hours. The reaction solution was quenched in an aqueous solution (50 mL), then extracted with dichloromethane (100 mL × 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 40-3 (2.5 g). MS (ESI) M / Z: 327.1 [M] + .

[0623] Step C: A solution of compound 40-3 (2.5 g, 7.62 mmol) in acetic acid (20 mL) was stirred at 85 °C for 1 hour. After returning to room temperature, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–10% ethyl acetate / n-hexane eluent gradient) to obtain compound 40-4 (310 mg). MS (ESI) M / Z: 255.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.17 (s, 1H), 8.12 (d, J = 2.26Hz, 1H), 7.90 (s, 1H), 6.71 (d, J = 1.51Hz, 1H), 3.98 (s, 3H).

[0624] Step D: A mixture of compound 40-4 (310 mg, 1.22 mmol), 2-mercaptoethanol (609.87 μL, 8.70 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (140.65 mg, 243.07 μmol), tris(dibenzylacetone)dipalladium (111.29 mg, 121.54 μmol), and N,N-diisopropylethylamine (471.22 mg, 3.65 mmol, 635.07 μL) in anhydrous dioxane (6 mL) was purged three times with nitrogen, and then stirred at 100 °C under nitrogen for 4 hours. After returning to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–48% ethyl acetate / n-hexane eluent gradient) to obtain compound 40-5 (140 mg). MS(ESI)M / Z:252.9[M+H] + .

[0625] Step E: N-iodosuccinimide (317.02 mg, 1.41 mmol) was added to a 6 mL acetonitrile solution of compound 40-5 (237 mg, 939.40 μmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered, the filter cake was collected, and concentrated under reduced pressure to obtain compound 40-6 (360 mg). MS (ESI) M / Z: 379.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.07(d,J=1.25Hz,1H),8.08(s,1H),7.64(d,J=1.25Hz,1H),3.98(s,3H),3.92(br s,2H),3.27(t,J=5.90Hz,2H),1.99-2.10(m,1H).

[0626] Step F: The mixture of compound 40-6 (250 mg, 661.05 μmol), cuprous iodide (75.54 mg, 396.63 μmol), 1,10-phenanthroline (59.56 mg, 330.53 μmol), and anhydrous cesium carbonate (646.15 mg, 1.98 mmol) in anhydrous toluene (15 mL) and DMF (4 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 110 °C under nitrogen for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–15% ethyl acetate / n-hexane eluent gradient) to obtain compound 40-7 (60 mg). MS (ESI) M / Z: 250.9 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 8.81 (d, J = 1.19 Hz, 1H), 7.85 (s, 1H), 7.36 (d, J = 1.19 Hz, 1H), 4.58-4.53 (m, 2H), 3.93 (s, 3H), 3.33-3.24 (m, 2H).

[0627] Step G: Under nitrogen protection, diethylaminosulfur trifluoride (23.76 μL, 179.80 μmol) was added to a mixed solution of compound 40-7 (90 mg, 359.61 μmol) in acetonitrile (3 mL) and dichloromethane (1.5 mL). This mixture was then slowly transferred dropwise to a solution of acetonitrile (1 mL) containing a selective fluorine reagent (152.87 mg, 431.53 μmol). The reaction mixture was then stirred at 20 °C for 1 hour. The reaction was quenched by pouring the solution into a saturated aqueous sodium bicarbonate solution (40 mL), extracted with ethyl acetate (60 mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-8 (140 mg). MS (ESI) M / Z: 269.1 [M+H] + .

[0628] Step H: Potassium persulfate complex salt (1.15 g, 1.86 mmol) was added to a mixed solution of compound 40-8 (100 mg, 372.77 μmol) in methanol (6 mL) and water (6 mL). The mixture was stirred at 20 °C for 12 hours, and then at 40 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL), and then extracted with dichloromethane (30 mL × 3) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate / n-hexane eluent gradient) to obtain compound 40-9 (28 mg). MS (ESI) M / Z: 301.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.17 (d, J = 1.07Hz, 1H), 8.28 (d, J = 1.07Hz, 1H), 8.03 (s, 1H), 5.73-5.51 (m, 1H), 5.02-4.84 (m, 2H), 4.00 (s, 3H).

[0629] Step I: Add tributyltin oxide (93.78 μL, 184.53 μmol) to a solution of compound 40-9 (15 mg, 49.95 μmol) in anhydrous toluene (0.5 mL). Stir the reaction solution at 105 °C for 12 hours. After cooling to room temperature, dilute the reaction solution with water (2 mL), adjust the pH to 4 with 2 M dilute hydrochloric acid, and then extract with ethyl acetate (6 mL × 3). Combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 40-10 (60 mg). MS (ESI) M / Z: 287.0 [M+H] + .

[0630] Step J: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.04 mg, 41.92 μmol) was added to a pyridine (1 mL) solution of compound 40-10 (40 mg, 27.95 μmol) and compound IE (12.94 mg, 30.64 μmol). The mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified twice by pre-HPLC (column type: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 50%-80%) and pre-TLC (dichloromethane / methanol = 15:1) to obtain compound 40 (5.7 mg). MS (ESI) M / Z: 618.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 9.27(br s,1H),9.19(s,1H),8.66(br d,J=8.28Hz,1H),8.39(br d,J=8.03Hz,1H),8.18(s,1H),8.07-8.03(m,1H),8.00(br d,J=6.53Hz,2H),7.86(br s,1H),7.72(t,J=7.78Hz,1H),6.79(d,J=8.53Hz,1H),5.77-5.57(m,1H),5.00(br d,J=4.02Hz,2H),4.97-4.82(m,2H),4.22(br d,J=12.30Hz,2H),3.86-3.70(m,2H),2.64(br t,J=11.54Hz,2H),1.34(br d,J=6.02Hz,6H).

[0631] Example 41 Preparation of Compound 41

[0632] Operating steps:

[0633] Step A: Lithium hydroxide monohydrate (111.04 mg, 2.65 mmol) was added to a tetrahydrofuran (4 mL) and water (1 mL) solution of compound 37-6 (132 mg, 441.06 μmol). The reaction solution was stirred at 20 °C for 3.5 hours. The reaction solution was diluted with water (10 mL), and the pH of the reaction solution was adjusted to 3 with 2 M dilute hydrochloric acid. The solution was then extracted with ethyl acetate (60 mL × 3), dried over anhydrous sodium sulfate, and the organic layers were combined, filtered, and concentrated under reduced pressure to obtain 90 mg of racemate. The racemate was chirally separated (DAICEL CHIRALCEL OD column (Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [carbon dioxide-ethanol (0.1% ammonia)]; gradient: 40%) to obtain compounds 41-1A (39 mg) and 41-1B (42 mg).

[0634] Compound 41-1A: SFC RT = 1.091 min; ee% = 100%; MS (ESI) M / Z: 286.1 [M+H] + .

[0635] Compound 41-1B: SFC RT = 1.406 min; ee% = 98.57; MS (ESI) M / Z: 286.1 [M+H] + .

[0636] Step B: To a pyridine (0.5 mL) solution of compound 41-1A (25 mg, 87.64 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 130.41 μmol) and 39-4 hydrochloride (40 mg, 108.15 μmol) were added. The mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; gradient: 27%-57%) to give compound 41 (24.9 mg). MS (ESI) M / Z: 601.2 [M+H] + . 1H NMR(400MHz,MeOH-d4)δppm 9.56(s,1H),9.05(d,J=1.2Hz,1H),8.77-8.71(m,2H),8.48(s,1H),8.26(d,J=9.6Hz,1H),8.08(d,J=2.4Hz,1H),7. 51(d,J=2.0Hz,1H),6.23-6.05(m,1H),5.29(ddd,J=2.8,9.2,15.2Hz,1H),5.20-5.10(m,1H),5.06(s,2H),4.54(br d,J=0.8Hz,4H),3.29-3.14(m,1H),2.92-2.74(m,1H),2.12-2.02(m,1H),1.19-1.10(m,2H),0.88-0.81(m,2H).

[0637] Example 42 Preparation of compounds 42A and 42B

[0638] Operating steps:

[0639] Step A: N-(tert-Butoxycarbonyl)-O-methylserine (3 g, 13.68 mmol) and dimethylhydroxylamine hydrochloride (1.88 g, 19.29 mmol) were dissolved in ultradry dichloromethane (50 mL) at room temperature. Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (9.78 g, 25.72 mmol) and N,N-diisopropylethylamine (6.1 g, 47.47 mmol) were added sequentially, and the system was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL) dropwise under ice bath conditions, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 42-2 (3 g). 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=8.3Hz,1H),4.72-4.60(m,1H),3.72(s,3H),3.42(dd,J=10.9,6.3Hz,2H),3.22(s,3H),3.10(s,3H),1.37(s,9H).

[0640] Step B: 42-2 (3 g, 11.45 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature and purged with nitrogen. The mixture was then cooled to below -40°C using dry ice / ethanol. Diisobutylaluminum hydride solution (28.6 mL, 28.6 mmol) was added dropwise, and the system was stirred for 2 hours. A saturated sodium potassium tartrate solution (30 mL) was added dropwise to quench the reaction, and the mixture was brought to room temperature and stirred for another 16 hours. After the system became clear, it was extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 42-3 (1.30 g). 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 7.26 (d, J = 7.3Hz, 1H), 4.15-4.05 (m, 1H), 3.63-3.56 (m, 2H), 3.23 (s, 3H), 1.39 (s, 9H).

[0641] Step C: Dimethyl (1.23 g, 6.4 mmol) phosphonate was slowly added dropwise to a methanol (20 mL) solution of compound 42-3 (1.3 g, 6.4 mmol) and potassium carbonate (1.76 g, 12.8 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The system was then filtered directly, and the mother liquor was concentrated to obtain the crude product, which was purified by column chromatography to obtain compound 42-4 (600 mg). 1 H NMR (400MHz, DMSO-d6) δ7.27(d,J=8.7Hz,1H),4.38(d,J=7.9Hz,1H),3.37(dd,J=6.8,1.7Hz,2H),3.25(s,3H),3.16(d,J=2.4Hz,1H),1.38(s,9H).

[0642] Step D: Compound 42-4 (600 mg, 3 mmol) and 2-bromo-6-chloronicotinaldehyde (663 mg, 3 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. Then, bis(triphenylphosphine)palladium dichloride (210 mg, 0.3 mmol), cuprous iodide (57 mg, 0.3 mmol), and triethylamine (918 mg, 9 mmol) were added sequentially. The system was then purged with nitrogen and heated to 70°C with stirring for 2 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 42-5 (360 mg). MS (ESI) M / Z: 283.0 [M-55] + .

[0643] Step E: Compound 42-5 (360 mg, 1.06 mmol) was dissolved in tert-butanol (10 mL) at room temperature, followed by the sequential addition of silver trifluoromethanesulfonate (26 mg, 0.1 mmol) and ammonium acetate (122 mg, 1.6 mmol). The system was then purged with nitrogen and stirred in the dark at room temperature for 3 hours. The crude product was directly concentrated and then purified by column chromatography to obtain compound 42-6 (147 mg). MS (ESI) M / Z: 338.2 [M+H] + .

[0644] Step F: To a mixture of compound 42-6 (95 mg, 291.2 mmol), hexamethyldistin (110.57 mg, 337.4 mmol, 69.98 μL) and toluene (6 mL), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (19.74 mg, 28.12 mmol) was added for degassing. The mixture was purged with nitrogen three times, and then stirred at 110 °C for 2 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain crude compound 42-7 (130 mg). MS (ESI) M / Z: 468.2 [M+H] + .

[0645] Step G: To a solution of compound 42-7 (128.98 mg, 276.68 μmol) and compound IF-2 (80 mg, 276.68 μmol) in dioxane (2 mL), dichlorobis(triphenylphosphine)palladium (19.42 mg, 27.67 μmol) was added for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluting buffer: 0-65% ethyl acetate / hexane gradient) to obtain compound 42-8 (110 mg). MS (ESI) M / Z: 512.2 [M+H] + .

[0646] Step H: Hydrochloric acid / dioxane solution (20 mL, 2 M) was added to compound 42-8 (90 mg, 175.92 μmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give compound 42-9 (70 mg). MS (ESI) M / Z: 412.2 [M+H] + .

[0647] Step I: To a pyridine (2 mL) solution of compound 42-9 (70 mg, 170.12 μmol) and compound 31-4A (53.81 mg, 170.12 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.92 mg, 255.18 μmol) was added for degassing. The mixture was purged with nitrogen three times, and then stirred at 50 °C for 1.5 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 52-Welch Xtimate C18 150 × 30 mm, 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; gradient: 58%-88%) to obtain compound 42-10 (70 mg). MS (ESI) M / Z: 710.4 [M+H] + .

[0648] Step J: Compound 42-10 (70 mg) was purified by SFC (column DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [carbon dioxide-ethanol:acetonitrile = 4:1 (0.1% ammonia)]; gradient: 50%) to obtain compound 42A (15.52 mg) and compound 42B (15.91 mg).

[0649] Compound 42A SFC: RT = 0.528 min; ee% = 100%. MS (ESI) M / Z: 710.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ9.50(br d,J=7.6Hz,1H),9.45(s,1H),9.04(s,1H),8.73-8.66(m,2H),8.63(d,J=8.4Hz,1H),8.03(s,1H),7.64(d,J=9.2Hz,1H),6.91(d,J=12 .0Hz,1H),6.15(dd,J=8.4,44.8Hz,1H),5.63(q,J=6.8Hz,1H),5.05-4.89(m,1H),4.77-4.60(m,1H),4.34(d,J=12.4Hz,2H),3.94(br d,J=6.4Hz,2H),3.73-3.60(m,2H),3.35(s,3H),2.58-2.52(m,2H),2.32-1.86(m,4H),1.20(d,J=6.4Hz,6H).

[0650] Compound 42A SFC: RT = 0.971 min; ee% = 99.41%. MS (ESI) M / Z: 710.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.50(d,J=8.0Hz,1H),9.45(s,1H),9.03(d,J=1.2Hz,1H),8.73-8.67(m,2H),8.63(d,J=8.8Hz,1H),8.03(s,1H),7.64 (dd,J=1.6,9.6Hz,1H),6.94-6.87(m,1H),6.14(dd,J=8.8,45.6Hz,1H),5.63(q,J=6.8Hz,1H),5.06-4.84(m,1H),4.80-4.61(m,1H),4.34(br d,J=12.8Hz,2H),3.94(br d,J=6.4Hz,2H),3.71-3.59(m,2H),3.35(s,3H),2.58-2.52(m,2H),2.26-1.88(m,4H),1.20(d,J=6.0Hz,6H).

[0651] Example 43 Preparation of compound 43

[0652] Operating steps:

[0653] Step A: To a mixture of compound 43-1 (13.5 g, 44.87 mmol) and methyl 4-mercaptobutyrate (6.02 g, 44.87 mmol) in dioxane (150 mL), tris(dibenzylacetone)dipalladium (3.29 g, 3.59 mmol), 45-bis(diphenylphosphine-99-dimethyloxaxanthracene) (5.19 g, 8.97 mmol), and N,N-diisopropylethylamine (15.63 mL, 89.73 mmol) were added. The mixture was stirred at 60 °C for 1.5 hours. After the reaction mixture cooled to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to rapid silica gel column chromatography (eluting with a 0–11% ethyl acetate / hexane gradient) to give compound 43-2 (14 g). 1 H NMR (400MHz, CDCl3) δppm 7.22(s,1H),7.04(dt,J=7.99,1.85Hz,1H),6.96(dt,J=9.06,1.85Hz,1H),3.70( s, 3H), 2.99 (t, J = 7.21Hz, 2H), 2.49 (t, J = 7.09Hz, 2H), 1.99 (quin, J = 7.15Hz, 2H).

[0654] Step B: Lithium hydroxide monohydrate (2M, 45.58mL) was added to a tetrahydrofuran (100mL) solution of compound 43-2 (14g, 45.58mmol), and the reaction mixture was stirred at 50°C for 1.5 hours. After the reaction mixture cooled to room temperature, the pH of the reaction mixture was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (300mL × 2). The combined organic layers were washed with brine (300mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 43-3 (13.5g). 1 H NMR (400MHz, CDCl3) δppm 7.23(s,1H),7.05(dt,J=7.99,1.91Hz,1H),6.96(dt,J=9.06,1.85Hz,1H), 3.01(t,J=7.27Hz,2H), 2.55(t,J=7.09Hz,2H), 2.00(quin,J=7.15Hz,2H).

[0655] Step C: Oxaloyl chloride (8.06 mL, 92.10 mmol) was added to a solution of compound 43-3 (13.5 g, 46.05 mmol) in dichloromethane (150 mL), and the mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 43-4 (14 g).

[0656] Step D: At 0°C, aluminum trichloride (7.37 mL, 134.79 mmol) was added to a solution of compound 43-4 (14 g, 44.93 mmol) in dichloromethane (250 mL), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched by slowly pouring it into water (400 mL) at 25°C and extracted with ethyl acetate (500 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative-grade HPLC (column: 58-Phenomenex Gemini NX C18 150 × 40 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 55%-75%) to give compound 43-5 (4.6 g). MS (ESI) M / Z: 274.9 [M+H] + &277.0[M+H+2] + . 1 H NMR (400MHz, CDCl3) δppm 7.42 (t, J = 1.25 Hz, 1H), 7.15 (dd, J = 9.54, 1.76 Hz, 1H), 2.98 (dt, J = 15.69, 6.46 Hz, 4H), 2.26 (quin, J = 6.53 Hz, 2H).

[0657] Step E: Sodium sulfide (1.96 g, 25.08 mmol, 1.05 mL) was added to a solution of compound 43-5 (4.6 g, 16.72 mmol) in N,N-dimethylformamide (40 mL) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched by slowly pouring it into a saturated aqueous solution of ammonium chloride (100 mL) at 25 °C and extracted with ethyl acetate (150 mL × 4). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was passed through a rapid silica gel column (eluting with a 0-10% ethyl acetate / hexane gradient) to give compound 43-6 (2.4 g). 1 H NMR (400MHz, CDCl3) δppm 7.42 (d, J = 1.76Hz, 1H), 7.33 (d, J = 1.51Hz, 1H), 4.09 (s, 1H), 2.99 (dt, J = 10.04, 6.65Hz, 4H), 2.26 (quin, J = 6.59Hz, 2H).

[0658] Step F: Pyridine (40 mL, 495.58 mmol) was added to an ethanol (40 mL) solution of compound 43-6 (2.4 g, 8.30 mmol) and hydroxylamine hydrochloride (1.73 g, 24.90 mmol), and the reaction mixture was stirred at 90 °C for 12 hours. After the reaction mixture cooled to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluting with a 0-3% ethyl acetate / hexane gradient) to give compound 43-7 (1.08 g). MS (ESI) M / Z: 285.9 [M+H] + &287.9[M+H+2] + . 1 H NMR (400MHz, CDCl3) δppm 7.84 (d, J = 1.51Hz, 1H), 7.53 (d, J = 1.25Hz, 1H), 3.53 (t, J = 6.65Hz, 2H), 3.20 (t, J = 7.03Hz, 2H), 2.29 (quin, J = 6.84Hz, 2H).

[0659] Step G: A methanol (20 mL) solution of compound 43-7 (1.08 g, 3.77 mmol) was degassed with [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (154.08 mg, 188.67 μmol) and triethylamine (1.05 mL, 7.55 mmol), and purged three times with carbon monoxide. The mixture was then stirred at 80 °C for 12 hours under a carbon monoxide (15 psi) atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluting with a 0-8% ethyl acetate / hexane gradient) to give compound 43-8 (920 mg). MS (ESI) M / Z: 266.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.38(d,J=1.19Hz,1H), 8.03(d,J=1.19Hz,1H), 3.97(s,3H), 3.59(t,J=6.62Hz,2H), 3.22(t,J=7.03Hz,2H), 2.32(quin,J=6.79Hz,2H).

[0660] Step H: Under a nitrogen atmosphere at 25°C, a solution of compound 43-8 (300 mg, 1.13 mmol) and diethylaminosulfur trifluoride (74.69 μL, 565.29 μmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) was slowly added in portions to a solution of dichloromethane (1 mL) containing a selective fluorine reagent (480.62 mg, 1.36 mmol). The reaction mixture was then stirred at 25°C for 1 hour. The reaction mixture was quenched dropwise with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 43-9 (300 mg), which was used directly in the next synthesis.

[0661] Step I: At 0°C, m-chloroperoxybenzoic acid (773.84 mg, 3.81 mmol, 85% purity) was added to a solution of compound 43-9 (360 mg, 1.27 mmol) in dichloromethane (10 mL). The reaction mixture was then stirred at 20°C for 12 hours. The reaction mixture was quenched by adding saturated sodium bicarbonate aqueous solution (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 87-Wepure PHS Phenyl 150 × 40 mm, 7 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 45%-75%) to give compound 43-10 (100 mg). 1 H NMR (400MHz, CDCl3) δppm 8.93(d,J=0.75Hz,1H),8.82(d,J=1.00Hz,1H),5.80-5.64(m,1H),4.05(s,3H),3.95(dd d,J=15.87,12.11,3.39Hz,1H),3.69-3.58(m,1H),3.07-2.92(m,1H),2.44-2.24(m,1H).

[0662] Step J: At 20°C, lithium hydroxide monohydrate (39.92 mg, 951.35 μmol) was added to a tetrahydrofuran (2 mL) and water (1 mL) solution of compound 43-10 (100 mg, 317.12 μmol), and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (3 mL) at 25°C, the aqueous phase was adjusted to pH 4 with 2 M hydrochloric acid, and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 43-11 (95 mg). MS (ESI) M / Z: 302.0 [M+H] + .1HNMR(400MHz,DMSO-d6)δppm 14.06-13.79(m,1H),9.29(d,J=1.26Hz,1H),8.50(d,J=1.25Hz,1H),6.42-6.26(m ,1H),3.69-3.59(m,1H),3.57-3.47(m,1H),3.03-2.86(m,1H),2.39-2.22(m,1H).

[0663] Step K: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90.66 mg, 472.93 μmol) was added to a pyridine (2 mL) solution of compound 43-11 (95 mg, 315.29 μmol) and compound IE (110.17 mg, 285.50 μmol). The reaction mixture was then stirred at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 87-Wepure PHS Phenyl 150 × 40 mm, 7 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 52%-82%) to give compound 43 (77 mg). MS (ESI) M / Z: 633.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δppm 9.31(s,1H),9.00(s,1H),8.69(s,1H),8.66-8.62(m,1H),8.59-8.56(m,1H),8.00(s,1H),7.90(d,J= 7.53Hz,1H),7.72(t,J=7.91Hz,1H),6.94(d,J=8.78Hz,1H),6.07-5.90(m,1H),4.97(s,2H),4.30(br d,J=13.05Hz,2H),3.89-3.70(m,3H),3.64-3.54(m,1H),3.08-2.93(m, 1H), 2.55 (t, J = 11.54Hz, 2H), 2.39-2.24 (m, 1H), 1.28 (d, J = 6.27Hz, 6H).

[0664] Example 44 Preparation of compounds 44A and 44B

[0665] Operating steps:

[0666] Step A: Compound 44-1 (3 g, 11.07 mmol) was dissolved in ultra-dry tetrahydrofuran (30 mL) at room temperature. After nitrogen purging, the system was cooled to -78 °C using dry ice and ethanol. Isopropyl magnesium chloride-lithium chloride solution (1.3 M, 16.6 mmol) was then slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, N,N-dimethylformamide (2.4 g, 33.21 mmol) was added dropwise, and the dry ice bath was removed, allowing the mixture to rise naturally to room temperature for another 2 hours. The reaction was quenched by adding saturated ammonium chloride solution (30 mL) to the system under ice bath conditions, and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain compound 44-2 (1.1 g). MS (ESI) M / Z: 357.2 [M+H] + .

[0667] Step B: Compound 44-2 (1 g, 2.79 mmol), N-(3-butyn-2-yl)carbamate tert-butyl ester (473.74 mg, 2.79 mmol), and cuprous iodide (53.2 mg, 0.28 mmol) were dissolved in ultradry N,N-dimethylformamide (20 mL) at room temperature. Then, bis(triphenylphosphine) palladium dichloride (196.28 mg, 0.28 mmol) and triethylamine (853.74 mg, 8.37 mmol) were added sequentially. After nitrogen purging, the system was heated to 70 °C in an oil bath and stirred for 2 hours. The system was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain compound 44-3 (980 mg). MS (ESI) M / Z: 309.2 [M+H] + .

[0668] Step C: Compound 44-3 (980 mg, 3.17 mmol) was dissolved in tert-butanol (10 mL) at room temperature, followed by the sequential addition of ammonium acetate (366.7 mg, 4.76 mmol) and silver tr...

Claims

1. The compound represented by Formula I, its pharmaceutically acceptable salt, or its stereoisomer: in, W represents C or N, and X1 represents chemical bonds, N, O, S, and =C(R). X1-1 - or -C(R) X1-2 )2-; R4 exists or does not exist; when R4 exists, X2 is CH, C, or N; when R4 does not exist, X2 is CH, C, N, or O. X3 is a chemical bond, -[CH(R) X3-1 )] m3 -、O、N(R X3-2 ), S, C 2-4 imide or C 2-4 Ethyne group; X4 is a chemical bond, -[CH(R) X4-1 )] m4 -、O、N(R X4-2 ) or -SO2-; X5 is a chemical bond, -[CH(R) X5-1 )] m5 -、O、N(R X5-2 ), S, -SO-, -SO2-, -SO(=N)-, -SO(R X5-3 )2-、-N=SO(R x5- 4) - or -C(O)-; where -N = SO(R) x5-4 The S atom of the )- group is attached to one end of the benzene ring; X6 is -[CH(R) X6-1 )] m6 -N(R) X6-2 ) or O; where R X6-1 For H, CN, OH, NH2, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; R X6-2 For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; X9 can be CH2, CF2, O, NH, S or N(CH3); R X1-1 R X1-2 R X3-1 R X3-2 R X4-1 R X4-2 R X5-1 R X5-2 R X5-3 R X5-4 Each is independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH or C 1-4 Alkyl-NH-CO-; or, one or two R X1-2 R X3-1 R X4-1 R X5-1 R X6-1 The atoms connected to it cyclize into 3-6 membered cycloalkanes; R1 and R2 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or the atoms of R1, R2, and R2 cyclized to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, C 1-4 Alkoxy, C 1-4 Alkylthio, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; R3 and R4 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl Alternatively, R3, R4, X1, X2, and the atoms connected to them may cyclize together to form a 5-7 membered cycloalkane ring, a 5-7 membered heterocycloalkane ring, a 5-10 membered heteroaryl ring, or a 6-10 membered aryl ring. The cyclized 5-7 membered cycloalkane ring or 5-7 membered heterocycloalkane ring can be fused with other 3-6 membered cycloalkane or 3-6 membered heterocycloalkane rings to form a 4-10 membered spirocyclic ring or a 4-10 membered heterospirocyclic ring; the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-7 membered cycloalkane, 5-7 membered heterocycloalkane, 5-10 membered heteroaryl, and 6-10 membered aryl are optionally further substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1- 4-Haloalkoxy, hydroxy-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl; R5 and R6 are independently designated as H and C in different regions. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy; or R5 co-cyclized with R3 and X1 to form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from the following: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl; Y2 is O, S, or NH; L1 is a -CONH-5-15-membered heteroaryl, 6-10-membered aryl, 5-15-membered heteroaryl, 6-13-membered cycloalkyl, or 6-13-membered heterocycloalkyl; wherein the 6-10-membered aryl, 5-15-membered heteroaryl, 6-13-membered cycloalkyl, and 6-13-membered heterocycloalkyl are optionally substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1- 4-alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl; Or, R 1 Or R 2 One of them co-cyclizes with L1 and its connected atoms to form a 5-7 membered cycloalkane ring or a 5-7 membered heterocycloalkane ring; L2 is a chemical bond, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyneyl, 3-6 membered cycloeneyl, 3-6 membered heterocycloeneyl or 5-6 membered heteroaryl; the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The ynyl group, 3-6-membered cycloalkyl group, 3-6-membered heteroalkyl group, and 5-6-membered heteroaryl group are optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; L3 is a 6-10 aryl, 5-12 heteroaryl, 6-10 cycloalkyl, or 6-10 heterocycloalkyl; R7 is a substituent of L3, selected from H, CN, OH, NH2, SF5, halogen, oxo, thio, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH, C 1-4 Alkyl-NH-CO- and The C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 The alkyl group -NH-CO- is optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4-alkoxy group, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 Alkyl-NH-CO-; m1, m2, m3, m4, m5, and m6 are independently 0, 1, 2, 3, or 4; n can be 0, 1, 2, 3 or 4 independently.

2. The compound of claim 1, its pharmaceutically acceptable salt, or its stereoisomer, wherein the compound satisfies one or more of the following conditions: (1) Two Rs X1-2 R X3-1 R X4-1 R X5-1 R X6-1 The atoms connected to it cyclize into 3-6 membered cycloalkanes; (2) L1 is a -CONH-5-15 heteroaryl group; (3) L2 is a 5-6 membered heteroaryl group; (4)R 1 Or R 2 One of them co-cyclizes with L1 and its connected atoms to form a 5-7 membered cycloalkane ring or a 5-7 membered heterocycloalkane ring; (5) R7 is a 3-10 membered heterocyclic alkyl group, preferably a 3-8 membered cycloalkyl group; (6) L2 is a chemical bond, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyneyl, 3-6 membered cycloalkylene, or 3-6 membered heteroalkylene; the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The ynyl group, 3-6 membered cycloalkyl group, and 3-6 membered heteroalkyl group may optionally be further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy groups; (7) R1 and R2 are each independently H, CN, OH, NH2, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or the atoms of R1, R2, and R2 cyclized to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, C 1-4 Alkylthio, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; (8) R7 is a substituent of L3, selected from H, CN, OH, NH2, SF5, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH, C 1-4 Alkyl-NH-CO- and The C 1-4 Alkyl, C 1- 4-Hydroalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 The alkyl group -NH-CO- is optionally further substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, thio, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-CO-, C 1-4 Alkyl-NH and C 1-4 Alkyl-NH-CO-; (9) R3 and R4 are each independently chemical bonds, H, CN, OH, NH2, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1- 4-alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or Alternatively, R3, R4, X1, X2, and the atoms connected to them can cyclize together to form a 5-7 membered cycloalkane ring, a 5-7 membered heterocycloalkane ring, or a 5-10 membered heteroaryl group. The cyclized 5-7 membered cycloalkane ring and 5-7 membered heterocycloalkane ring can be fused with other 3-6 membered cycloalkane or 3-6 membered heterocycloalkane ring to form a 4-10 membered spirocyclic ring or a 4-10 membered heterospirocyclic ring; the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-7 membered cycloalkane, 5-7 membered heterocycloalkane, and 5-10 membered heteroaryl are optionally further substituted by one or more groups selected from the following: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl.

3. The compound of formula I as described in claim 1 or 2, its pharmaceutically acceptable salt, or its stereoisomer, wherein, The compound represented by Formula I is a compound represented by Formula Ia or Formula Ib, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; X3, X4, X5, X6, X9, Y2, L1, L2, L3, and n have the same meaning as in any one of claims 1-2.

4. The compound of claim 3, its pharmaceutically acceptable salt, or its stereoisomer, wherein, for Where X7 represents chemical bonds, O, N, S, =C(R) X7-1 )-、-C(R X7-2 )2- or N(R X7- 3); X8 represents chemical bonds, O, N, S, =C(R) X8-1 )-、-C(R X8-2 )2- or N(R X8-3 ); R X7-1 R X7-2 R X7-3 R X8-1 R X8-2 R X8-3 Each independently constitutes a chemical bond, H, CN, OH, NH2, halogen, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or two R X7-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or the two R atoms are cyclized into cycloalkyl or heterocycloalkyl. X8-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or R X7-2 R X8-2 The atoms connected to it are cyclized into 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by one or more groups selected from the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl-C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group and 5-10 membered heteroaryl group; preferably, X1 is selected from N, =C(R X1-1 )-、-C(R X1-1 )2-, S or O; X2 is selected from N or CH; X7 is selected from =C(R X7-1 )-、-C(R X7-2 X2- or N; X8 is a chemical bond or CH2; X9 is selected from O or CH2; more preferably, X1 is selected from N, =CH-, =CF-, -CH2-, S or O; X7 is selected from =CH-, =CF-, -CH2-, N or O.

5. The compound of claim 3 or 4, its pharmaceutically acceptable salt, or its stereoisomer, wherein, It satisfies one or more of the following conditions: for Preferably, X1 is 0 and X2 is N; or for Preferably, X1 is N or = C(R) X1- 1)-;R X1-1 H, halogen or C 1-4 Alkyl; X2 is N or CH; X3 is -[CH(R)] X3-1 )] m3 -、O or N(R) X3-2 ); R X3-1 and R X3-2 Each is independently H, halogen, or C 1-4 Alkyl group; X4 is a chemical bond, CHR X4-1 、N(R X4-2 ) or O; the R X4-1 H, halogen, C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy; or R X4-1 The atoms commonly bonded to it cyclize together to form cyclopropyl or cyclobutyl groups; the R X4-2 For H, C 1-4 Alkyl or C 1-4 Haloalkyl; X5 is a chemical bond, -SO2-, -SO(=N)-, -SO(CH3)2- or -N=SO(CH3)-, wherein the S atom of -N=SO(CH3)- is attached to a benzene ring; X7 is N or =C(R X7-1 )-;R X7-1 H, halogen or C 1-4 Alkyl; X9 is CH2 or O; preferably, X1 is N or =C(R) X1-1 )-;R X1-1 It is a halogen; X4 is CHR. X4-1 R X4-1 H, halogen or C 1-4 Alkyl; X7 is N or =C(R) X7-1 )-;R X7-1 It can be H, F, Cl, Br, methyl, or ethyl.

6. The compound according to any one of claims 3-5, its pharmaceutically acceptable salt, or its stereoisomer, wherein, It satisfies one or more of the following conditions: (a1)X1 is N, =CH-, =CCH3- or =CF-, preferably N or =CF-; (a2)X2 is N; (a3)X3 is -CH2- or -CH2CH2-; (a4)X4 is a chemical bond, CH2, CHF, NH or N(CH3); or R X4-1 The atoms connected to it are cyclized to cyclopropyl groups; preferably, X4 is CH2 or CHF. (a5) X5 is -SO2-, -SO(=N)- or -N=SO(CH3)-; preferably, X5 is -SO2-; (a6)X7 is N, =CH-, =CF- or =CCH3-; (a7)X9 is CH2.

7. The compound according to any one of claims 1-6, its pharmaceutically acceptable salt, or its stereoisomer, wherein, (1) Y2 is 0; (2) X6 is N(R) X6-1 ), R X6-1 Independently for H and C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; (3) R1 and R2 are independently H, OH, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to are cyclized together to form cyclopropyl or cyclobutyl; wherein the cyclopropyl or cyclobutyl is optionally further substituted by one or more groups selected from the following: CN, F, Cl, NH2, OH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and hydroxy-C 1-4 alkyl; (4) L1 is Among them, R L1 Each of these elements independently represents H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or hydroxy-C 1-4 Alkyl group; q is 0, 1, 2 or 3; (5) L2 is a chemical bond, C 1-4 Alkylene, C 1-4 imidene group, C 1-4 The group is alkynyl, 3-6-membered cycloalkylene, 3-6-membered heteroalkylene, or 5-6-membered heteroaryl, and optionally substituted with one or more groups selected from: CN, halogen, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; (6) L3 is pyridine, Among them, A1, A2, and A3 are each independently chemical bonds, CH2, O, S, NH, or -C(=O)-, preferably CH2, O, S, or NH; A4 is N or CH; A5, A6, and A7 are each independently chemical bonds, N or CH, preferably N or CH; A8 is CH2, S, or O; (7) R7 is a substituent of L3, selected from H, halogens, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, or 5-10-membered heteroaryl; wherein the 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, or 5-10-membered heteroaryl is optionally further substituted by one or more groups selected from: OH, oxo, halogen, C 1-4 Alkyl or C 1-4 Alkoxy; (8) n is 1 or 2.

8. The compound of claim 7, its pharmaceutically acceptable salt, or its stereoisomer, wherein, (1) X6 is N(R) X6-1 ), R X6-1 Independently H or C 1-4 alkyl; (2) R1 and R2 are independently H, OH, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl or 3-6 heterocyclic alkyl; (3) L1 is Among them, R L1 CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or hydroxy-C 1-4 Alkyl group; q is 0, 1, 2 or 3; (4) L2 is a chemical bond, C 1-4 Alkylene, C 1-4 imidene group, C 1-4 The group is alkynyl, 3-6 membered cycloalkylene, or 3-6 membered heteroalkylene, and optionally substituted with one or more groups selected from: CN, halogen, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; (5) L3 is pyridine, Wherein, A1, A2, and A3 are each independently a chemical bond, CH2, O, S, or NH, preferably CH2, O, S, or NH; A4 is N or CH; A5, A6, and A7 are each independently a chemical bond, N or CH, preferably N or CH; A8 is CH2, S, or O; preferably, L3 is pyridine or Among them, A1, A2, and A3 are each independently CH2, O, S, or NH; A4 is N or CH; A5, A6, and A7 are each independently N or CH.

9. The compound of claim 8, its pharmaceutically acceptable salt, or its stereoisomer, wherein, It satisfies one or more of the following conditions: (1) X6 is NH or N(CH3); (2) R1 and R2 are both H; or R1 is methyl, methoxymethyl, methoxyethyl, ethoxymethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, and R2 is H; or R1, R2 and the atoms they are attached to cyclize together to form cyclopropyl; (3) L1 is Preferably, L1 is One end marked with an asterisk * is connected to one side of L2 or L3; (4) L2 represents chemical bonds, ethylene, 1-fluoro-ethylene, vinylene, ethynylene, cyclobutane, Preferably, L2 is (5) L3 is Preferably, L3 is (6) R7 is F, methyl, oxo, thio, cyclopropyl, 3,5-dimethyl-morpholin-1-yl, difluoromethyl, 1,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, methoxyethyl, Preferably, R7 is 3,5-dimethylmorpholin-1-yl.

10. The compound according to any one of claims 3-9, its pharmaceutically acceptable salt, or its stereoisomer, wherein, for Wherein, X5 is -SO2- or a chemical bond; Alternatively, -L1-L2- can be one of the following groups: The end marked with an asterisk (*) is connected to the L3 side.

11. The compound of claim 10, its pharmaceutically acceptable salt, or its stereoisomer, wherein, for Alternatively, -L1-L2-L3 can be one of the following groups: Among the markings One end is L1 side.

12. The compound according to any one of claims 1-11, its pharmaceutically acceptable salt, or its stereoisomer, wherein, It is a compound of Formula II, its pharmaceutically acceptable salt, or a stereoisomer thereof; it is any of the following compounds, its pharmaceutically acceptable salt, or a stereoisomer thereof: The definitions of each letter and group are as described in any one of claims 1-11.

13. The compound according to any one of claims 1-12, its pharmaceutically acceptable salt, or its stereoisomer, wherein it is a compound, its pharmaceutically acceptable salt, or its stereoisomer:

14. A pharmaceutical composition comprising the compound as claimed in any one of claims 1-13 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and any pharmaceutically acceptable carrier.

15. The use of a compound as described in any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a composition as described in claim 14, in the preparation of a medicament for treating diseases associated with mutations in the SMARCA2 and / or SMARCA4 genes; wherein the diseases associated with mutations in the SMARCA2 and / or SMARCA4 genes may be ovarian cancer, urothelial carcinoma, non-small cell lung cancer, gastric cancer, sarcoma, melanoma, head and neck cancer, liver cancer, cervical cancer, or bile duct cancer associated with mutations in the SMARCA2 and / or SMARCA4 genes.

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