WEE1 inhibitors and their production and use

Abstract

The present invention relates to compounds of formula 1, their stereoisomers, or pharma- ceutically acceptable salts, and their use in the manufacture of a medicament for treating diseases associated with WEE1 activity. TIFF2025503478000259.tif40170

Description

[Technical field]

[0001] The present application relates to compounds that inhibit WEE1 kinase activity, in particular compounds represented by formula 1, or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, and further to methods for the preparation of these compounds and pharmaceutical compositions and their use in the manufacture of medicaments for treating diseases associated with WEE1 activity. [Background technology]

[0002] WEE1 tyrosine kinase is a cell cycle G2 checkpoint. If the cell cycle is tightly controlled and the cell's DNA is not damaged, the G1, S and G2 checkpoints will encourage the cell to enter the mitotic phase and ensure that the cell cycle is completed successfully (Clinical Cancer Research,2011,17(13):4200-4207.). The cell cycle is controlled by cyclin-dependent kinases (CDKs), and the CDK family includes 14 serine / threonine protein kinases. CDK activity is controlled by phosphorylation and binding to different cyclins. The cellular transition from G2 to mitotic phase is positively regulated by phosphorylation of CDK1 (also called CDC2) and the associated cyclin B. Before cell division, CDK1 is in an inactive state and is phosphorylated at tyrosine 15 by WEE1 and at threonine 14 by myelin transcription factor (MYT1). Therefore, WEE1 is a negative regulator of the cell cycle, and by blocking cyclin B and the activated CDK1 complex from entering the cell nucleus, it negatively regulates the transition of cells from the G2 phase to the mitotic phase. The expression and activity of WEE1 are increased in the S and G2 phases, and decreased in the M phase where it is highly phosphorylated. When cells are in the G2 phase and no DNA damage has occurred, polo-like kinase 1 (PLK1) phosphorylates WEE1, which is then degraded by the ubiquitin ligase complex. PLK1 also phosphorylates and activates the protein phosphatase cell division cycle 25 homolog (CDC25), which activates CDK1 by dephosphorylation. Active CDK1 can bind to cyclin B and promote the transition of cells to the mitotic phase (Molecular&Cellular Biology,2012,32(20):4226.).

[0003] If the DNA of a cell is damaged, the G1, S, and G2 checkpoints delay the cell's mitotic transition, allowing time for the damaged DNA to be repaired before the cell begins to divide, ensuring genomic integrity. P53, a key regulator of the G1 checkpoint, is mutated in many malignant tumor cells (Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(10):3753-3758.). Tumor cells with defective P53 function are unable to arrest the cell cycle in the G1 phase even when DNA is damaged, making them more dependent on the G2 checkpoint. In response to DNA damage, the G2 checkpoint delays the cell's mitotic transition by inhibiting the phosphorylation of CDK1 through two parallel but related pathways. Depending on the type of DNA damage, ataxia telangiectasia mutated (ATM) or ataxia telangiectasia related (ATR) protein kinases are activated (Oncotarget, 2016, 7(31):49902-49916.). ATM is activated by ionizing radiation, radioactive materials, or agents that cause double-stranded DNA breaks. ATM phosphorylates and activates checkpoint kinase 2 (CHK2), which phosphorylates cell division cycle 25C phosphatase (CDC25C) at Ser216. This leads to the nuclear export and segregation of CDC25C from the cytoplasm, inhibiting its phosphorylation activity. Inhibition of CDC25C activity inhibits phosphorylation of the CDK1 / CDK2-bound cyclin B complex, inactivating CDK1, and inhibiting cell mitosis (Molecular Cancer,2014,13(1):72.). ATR is generally activated by genotoxic stimuli that cause single-stranded DNA breaks. ATR is the major kinase that phosphorylates and activates CHK1. CHK1 is activated by ATM or ATR, whereas CHK2 is activated only by ATM. CHK1 also phosphorylates WEE1 and CDC25C, activating WEE1 kinase activity and inhibiting CDC25C phosphatase activity. WEE1 phosphorylates CDK1-bound cyclin B, arresting the cell cycle in G2 phase to allow time for DNA repair (Drug News&Perspectives,2010,23(7):425.).

[0004] WEE1 is overexpressed in many malignant tumors, including liver cancer, breast cancer, malignant neuroma, melanoma, and adult and pediatric brain tumors. Some of these tumor cells have abnormal G1 checkpoints, and inhibition of WEE1 activity leads to a breakdown in the G2 checkpoint, leading to continued division and eventual death of cells with unrepaired DNA (Molecular Cancer Therapeutics,2013,12(12):2675-2684.). Inhibition of WEE1 activity, whether by pyrimidine derivatives (PD0166285) or small interfering RNA knockdown, renders ovarian, colon, uterine, osteosarcoma, malignant neuroma, and lung cancer cells more sensitive to DNA damage induced by radiation or topoisomerase inhibition. Therefore, WEE1 inhibitors, either alone or in combination, are expected to be widely used (Cancer Biology&Therapy,2010,9(7):523-525.). Patent Documents 1 to 11, etc., describe small molecule compounds having WEE1 kinase inhibitory activity. The most promising compound at present is AZD1775, which has already been subjected to Phase II clinical trials and has been confirmed to have excellent cancer therapeutic effects. However, AZD1775 shows obvious adverse reactions, and in order to further improve its pharmaceutical activity and therapeutic effect, a WEE1 inhibitor with better safety and a wider range of application is required. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 126122 [Patent Document 2] International Publication No. 2008 / 133866 [Patent Document 3] International Publication No. 2013 / 012681 [Patent Document 4] International Publication No. 2013 / 126656 [Patent Document 5] International Publication No. 2014 / 167347 [Patent Document 6] International Publication No. 2015 / 092431 [Patent Document 7] International Publication No. 2018 / 011569 [Patent Document 8] International Publication No. 2018 / 011570 [Patent Document 9] International Publication No. 2018 / 090939 [Patent Document 10] International Publication No. 2018 / 133829 [Patent Document 11] International Publication No. 2018 / 171633 Summary of the Invention

[0006] An object of the present invention is to provide a compound represented by formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF2025503478000002.tif40170 [R1 is -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 0~2 Alkylene groups -CN, -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 alkylene groups, -(3- to 10-membered heterocycloalkyl groups); 0~2 Alkylene group, -C 1~6Alkyl group, -C 2~6 Alkenyl group, -C 2~6 The alkynyl group, the 3- to 10-membered cycloalkyl group, and the 3- to 10-membered heterocycloalkyl group may further comprise one, two, three, or four independent R 11 may be substituted with R 11 But hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 selected from the group consisting of alkyl groups and halogens; R2 is selected from the group consisting of formula 2; TIFF2025503478000003.tif123170R 21 But hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -C 0~2 Alkylene group -C(O)OC 1~6 Alkyl group, -C 0~2 Alkylene groups -COOH, -C(O)C 1~6 selected from the group consisting of alkyl groups and halogens; R3 is selected from the group consisting of formula 3; TIFF2025503478000004.tif207170X1 is a chemical bond, O, NR N1 or CR C1 R C2 X2 is selected from the group consisting of N or CR C1 X3 is selected from the group consisting of O, NR N1 or CR C1 R C2 Selected from the group consisting of n is selected from the group consisting of 1, 2 or 3; R N1 However, hydrogen, halogens, -OH, -C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C(O)(C 1~6alkyl groups), R C1 , R C2 are each independently hydrogen, halogen, cyano group, nitro group, -OH, -C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 Alkyl group)(C 1~6 alkyl groups), R4 is selected from the group consisting of -(5-12 membered bridged heterocycloalkyl groups), and the bridged heterocycloalkyl group is further selected from one, two, three or four independent R 41 may be substituted with R 41 is hydrogen, oxo, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, halogen-substituted C 1~6 C substituted with alkyl or hydroxy groups 1~6 Alkyl group, halogen, cyano group, nitro group, -OH, -C 0~2 Alkylene group -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -C(O)R 42 , -C 0~2 Alkylene group -C(O)NR 42 R 43 , -C 0~2 Alkylene group -C(O)OR 42 , -C 0~2 Alkylene group -S(O)R 42 , -C 0~2 Alkylene group -S(O)NR 42 R 43 , -C 0~2Alkylene group -S(O)OR 42 , -C 0~2 Alkylene group -S(O)R 42 , -C 0~2 Alkylene group -S(O)NR 42 R 43 , -C 0~2 Alkylene group -S(O)OR 42 , -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 alkylene group-(5-10 membered heteroaryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, the aryl ring, and the heteroaryl ring further comprise one, two, three, or four independent R 44 may be substituted with R 42 , R 43 are each independently hydrogen, halogen, cyano group, nitro group, -OH, -C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 alkylene group-(5-10 membered heteroaryl ring), R 44 is hydrogen, oxo, halogen, cyano group, nitro group, -OH, -C 1~6 Alkyl group, halogen substituted -C 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl groups), Or, R 41 , R C1 or R C2 form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring together with the atom directly connected thereto; R 5 are hydrogen, oxo, halogen, cyano group, nitro group, -OH, -NH2, -C 1~6 C substituted with alkyl groups and halogens 1~6 C substituted with alkyl or hydroxy groups 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -OC 0~2 Alkylene group -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -O-(3-10 membered cycloalkyl group), -OC 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 alkylene group-(5-10 membered heteroaryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, the aryl ring, and the heteroaryl ring further comprise one, two, three, or four independent R 51 may be substituted with The above R 51 But hydrogen, C 1~6C substituted with alkyl groups and halogens 1~6 Alkyl group, oxo, halogen, cyano group, nitro group, -OH, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -C 0~2 Alkylene group -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl groups), Each R6 is independently hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, halogen, cyano group, nitro group, -OH, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 Alkylene group -(5-10 membered heteroaryl ring), -C 0~2 Alkylene group -(5-12 membered spiro ring), -C 0~2 Alkylene group -(5-12 membered spiro heterocycle), -C 0~2 Alkylene group -(5-12 membered bridged ring), -C 0~2 alkylene group-(5-12 membered bridged heterocycle), wherein the ring A is selected from the group consisting of a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, and a 5- to 12-membered bridged heterocycle, wherein the spiro ring, spiro heterocycle, bridged ring, and bridged heterocycle further comprise one, two, three, or four independent R A1 may be substituted with Each R A1 are each independently hydrogen, halogen, cyano group, nitro group, -OH, -C 1~6 C substituted with alkyl groups and halogens1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 Alkylene group -(5-10 membered heteroaryl ring), -C 0~2 Alkylene group -(5-12 membered spiro ring), -C 0~2 Alkylene group -(5-12 membered spiro heterocycle), -C 0~2 Alkylene group -(5-12 membered bridged ring), -C 0~2 wherein ring B is selected from the group consisting of a 3- to 10-membered carbocycle, a 3- to 10-membered heterocycle, a 5- to 10-membered aryl ring, a 5- to 10-membered heteroaryl ring, a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, a 5- to 12-membered bridged heterocycle, a 3- to 10-membered fused ring, and a 3- to 10-membered fused heterocycle, wherein the carbocycle, heterocycle, aryl ring, heteroaryl ring, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle, fused ring, and fused heterocycle are further selected from the group consisting of one, two, three, or four independent R B1 may be substituted with Each R B1 are each independently hydrogen, -C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, halogen, cyano group, nitro group, -OH, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 alkylene group-(5-10 membered heteroaryl ring), R7 and R8 are each independently hydrogen, halogen, cyano, nitro, -OH, -C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 alkylene group-(5-10 membered heteroaryl ring), Alternatively, R7 and R8 together with the atom directly connected thereto form a 3- to 10-membered fused ring, a 3- to 10-membered fused heterocyclic ring, a 3- to 10-membered spiro ring, or a 3- to 10-membered spiro heterocyclic ring, and the fused ring, fused heterocyclic ring, spiro ring, or spiro heterocyclic ring further comprises one, two, three, or four independent R 71 may be substituted with Each R 71 are independently hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, halogen, cyano group, nitro group, -OH, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl groups), wherein ring C is selected from the group consisting of a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, a 5- to 12-membered bridged heterocycle, a 3- to 10-membered fused ring, and a 3- to 10-membered fused heterocycle, wherein the spiro ring, spiro heterocycle, bridged ring, bridged heterocycle, fused ring, and fused heterocycle further comprise one, two, three, or four independent R C1 may be substituted with Each R C1 are each independently hydrogen, halogen, cyano group, nitro group, -OH, C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl group), -C 0~2 Alkylene group -(3-10 membered cycloalkyl group), -C 0~2 Alkylene group -(3-10 membered heterocycloalkyl group), -C 0~2 Alkylene group -(5-10 membered aryl ring), -C 0~2 Alkylene group -(5-10 membered heteroaryl ring), -C 0~2 Alkylene group -(5-12 membered spiro ring), -C 0~2 Alkylene group -(5-12 membered spiro heterocycle), -C 0~2 Alkylene group -(5-12 membered bridged ring), -C 0~2 alkylene group-(5-12 membered bridged heterocycle), R 10 But hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 alkyl groups, R9 is -C 0~2 Alkylene group -C(O)NR 91 R 92 , -C(O)C 1~6 alkyl groups, each R 91 , R 92 are independently hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6alkyl groups, Or, R 91 , R 92 together with the atom(s) directly connected thereto form a 3- to 10-membered heterocyclic ring, the heterocyclic ring further comprising one, two, three or four independent R 93 may be substituted with Each R 93 are independently hydrogen, C 1~6 C substituted with alkyl groups and halogens 1~6 Alkyl group, halogen, cyano group, nitro group, -OH, -O(C 1~6 alkyl group), -O(C substituted with halogen 1~6 alkyl group), -NH2, -NH(C 1~6 alkyl group), -N(C 1~6 Alkyl group)(C 1~6 alkyl groups), When R3 is formula 4, the B ring is a 3-membered carbocyclic ring, and R1 is formula 5, R2 is not formula 6; TIFF2025503478000005.tif51170TIFF2025503478000006.tif22170TIFF2025503478000007.tif31170When R3 is a compound of formula 7, R7 and R8 are each hydrogen, and R1 is a compound of formula 8, R2 is not a compound of formula 9, TIFF2025503478000008.tif47170TIFF2025503478000009.tif22170TIFF2025503478000010.tif29170If R3 is a formula 10, X1 is a bond, R4 is a formula 11, and R1 is a formula 12, then R2 is not a formula 13, TIFF2025503478000011.tif41170TIFF2025503478000012.tif34170TIFF2025503478000013.tif22170TIFF2025503478000014.tif31170If R3 is formula 14, X1 is a bond, R4 is formula 15, and R1 is formula 16, then R2 is not formula 17; TIFF2025503478000015.tif41170TIFF2025503478000016.tif34170TIFF2025503478000017.tif22170TIFF2025503478000018.tif33170If R3 is equation 18 and R1 is equation 19, then R2 is equation 20; TIFF2025503478000019.tif49170TIFF2025503478000020.tif22170TIFF2025503478000021.tif45170If R3 is formula 21 and R1 is formula 22, then R2 is not formula 23, TIFF2025503478000022.tif52170TIFF2025503478000023.tif22170TIFF2025503478000024.tif36170R2 is formula 24, R 21 is methyl and R1 is of formula 25, then R3 is not of formula 26; TIFF2025503478000025.tif33170TIFF2025503478000026.tif22170TIFF2025503478000027.tif65170R2 is formula 27, R 21 is hydrogen and R1 is of formula 28, then R3 is not of formula 29; TIFF2025503478000028.tif34170TIFF2025503478000029.tif22170TIFF2025503478000030.tif49170R2 is formula 30, R 21 is hydrogen and R1 is of formula 31, then R3 is not of formula 32; TIFF2025503478000031.tif29170TIFF2025503478000032.tif22170TIFF2025503478000033.tif57170R2 is formula 33, R 21 is hydrogen and R1 is of formula 34, then R3 is not of formula 35; TIFF2025503478000034.tif37170TIFF2025503478000035.tif22170TIFF2025503478000036.tif49170If R2 is formula 36 and R1 is formula 37, then R3 is not formula 38.] TIFF2025503478000037.tif31170TIFF2025503478000038.tif22170TIFF2025503478000039.tif57170

[0007] Preferably, the compound according to the invention, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, is such that R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, Formula 39. TIFF2025503478000040.tif30170

[0008] Preferably, the compound according to the invention, its stereoisomer, or its pharma- ceutically acceptable salt, is such that R2 is selected from the group consisting of formula 40. TIFF2025503478000041.tif123170

[0009] Preferably, the compounds according to the invention, their stereoisomers, or their pharma- ceutically acceptable salts, are those in which X1 is a chemical bond, O, NR N1 or CR C1 R C2 R C1 , R C2 are independently hydrogen, C 1~3 Alkyl groups, halogens, halogen-substituted C 1~3 Alkyl group, -C 1~2 Alkylene group -N(C 1~6 Alkyl group)(C 1~6 alkyl group), R N1 But hydrogen, C 1~3 C substituted with alkyl groups and halogens 1~3 It is selected from the group consisting of alkyl groups and -(3- to 10-membered heterocycloalkyl groups).

[0010] Preferably, the compound according to the invention, its stereoisomer, or its pharma- ceutically acceptable salt, is a compound in which R4 is selected from the group consisting of formula 41, in which X is O, NR 41 X4 is selected from the group consisting of O, NH or CH2, n1 is selected from the group consisting of 1 or 2, and said R4 is further selected from the group consisting of one, two, three or four independent R 41 and R 41 But hydrogen, oxo, C 1~3 Alkyl group, -C 2~6 Alkenyl group, halogen-substituted C 1~3 C substituted with alkyl or hydroxy groups 1~6 Alkyl group, -C 0~2 Alkylene group -O(C 1~3 alkyl group), -NH2, -NH(C 1~3 alkyl group), -N(C 1~3 Alkyl group)(C 1~3 alkyl group), -C(O)R 42 , -C(O)NR 42 R 43 , -C(O)OR 42 , -(3- to 10-membered cycloalkyl group), -(3- to 10-membered heterocycloalkyl group), -C 1~2 alkylene group-(5-10 membered aryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, and the aryl ring are further selected from the group consisting of one, two, three, or four independent R 44 and R 42 , R 43 are independently hydrogen, halogen, -OH, C 1~3 C substituted with alkyl groups and halogens 1~3 alkyl groups; R 44 But hydrogen, C 1~3 C substituted with alkyl groups and halogens 1~3 Alkyl group, -O(C 1~3 alkyl group). TIFF2025503478000042.tif38170

[0011] Preferably, the compounds according to the invention, their stereoisomers, or pharma- ceutically acceptable salts thereof, are those in which R4 is selected from the group consisting of formula 42. TIFF2025503478000043.tif195170

[0012] Preferably, the compounds according to the invention, their stereoisomers, or their pharma- ceutically acceptable salts are those in which R5 is hydrogen, halogen, -C 1~3 C substituted with alkyl groups and halogens 1~3 C substituted with alkyl or hydroxy groups 1~3 Alkyl group, -O(C 1~3 alkyl group), -NH(C 1~3 alkyl group), -O-C2 alkylene group -N(C 1~3 Alkyl group)(C 1~3 wherein the alkyl group, alkylene group, cycloalkyl group, and heterocycloalkyl group are further selected from the group consisting of one, two, three, or four independent R 51 and R 51 But hydrogen, C 1~3 C substituted with alkyl groups and halogens 1~3 The alkyl group is selected from the group consisting of alkyl groups.

[0013] Preferably, in the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, R5 is selected from the group consisting of methyl, ethyl, ethoxy, F, methyl substituted with a hydroxy group, formula 43. TIFF2025503478000044.tif37170

[0014] Preferably, the compounds according to the invention, their stereoisomers, or their pharma- ceutically acceptable salts are those in which R6 is hydrogen, C 1~3 Alkyl group, -NH(C 1~3 alkyl group), -N(C 1~3 Alkyl group)(C 1~3 alkyl group).

[0015] Preferably, the compounds according to the invention, their stereoisomers, or pharma- ceutically acceptable salts thereof, have the A ring selected from the group consisting of formula 44. TIFF2025503478000045.tif27170

[0016] Preferably, in the compound, its stereoisomer, or its pharma- ceutically acceptable salt according to the present invention, ring B is selected from the group consisting of a 3- to 10-membered heterocycle, a 5- to 12-membered bridged heterocycle, and a 3- to 10-membered fused heterocycle, wherein the heterocycle, bridged heterocycle, and fused heterocycle further comprise one, two, three, or four independent R B1 Each R B1 are independently hydrogen, C 1~3 C substituted with alkyl groups and halogens 1~3 The alkyl group is selected from the group consisting of alkyl groups. Additionally, the B ring is selected from the group consisting of formula 45. TIFF2025503478000046.tif34170

[0017] Preferably, the compounds according to the invention, their stereoisomers, or pharma- ceutically acceptable salts thereof, have the C-ring selected from the group consisting of formula 46. TIFF2025503478000047.tif32170

[0018] Preferably, the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, is such that R7 and R8 are each independently selected from the group consisting of formula 47, or R7 and R8 together with the atom to which they are directly linked form formula 48. TIFF2025503478000048.tif28170TIFF2025503478000049.tif32170

[0019] Preferably, the compound according to the invention, its stereoisomer, or a pharma- ceutically acceptable salt thereof, is wherein R3 is selected from the group consisting of formula 49. TIFF2025503478000050.tif255169TIFF2025503478000051.tif255170TIFF2025503478000052.tif156170

[0020] Preferably, the compound according to the invention, its stereoisomer, or a pharma- ceutically acceptable salt thereof, is a compound according to formula I, [Table 1] TIFF2025503478000054.tif215170TIFF2025503478000055.tif190170TIFF20255034780 00056.tif221170TIFF2025503478000057.tif203170TIFF2025503478000058.tif245170 TIFF2025503478000059.tif227170TIFF2025503478000060.tif221170TIFF20255034780 00061.tif252170TIFF2025503478000062.tif203170TIFF2025503478000063.tif221169 TIFF2025503478000064.tif251170TIFF2025503478000065.tif245170TIFF20255034780 00066.tif227170TIFF2025503478000067.tif215170TIFF2025503478000068.tif233170 TIFF2025503478000069.tif221170TIFF2025503478000070.tif221170TIFF20255034780 00071.tif227170TIFF2025503478000072.tif233170TIFF2025503478000073.tif233170

[0021] Preferably, the compound of the present invention, its stereoisomer, or its pharma- ceutically acceptable salt is characterized in that the compound described by formula 1 is: [Table 2] TIFF2025503478000075.tif209170TIFF2025503478000076.tif252170TIFF2025503478000077.tif239170TIFF2025503478000078.tif245170

[0022] Preferably, the compounds of the present invention, their stereoisomers and their pharma- ceutically acceptable salts are characterized in that the compound described by formula 1 is: [Table 3]

[0023] The present invention further provides the use of any of the above described compounds, or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, in the manufacture of a medicament for treating a disease mediated by WEE1. The WEE1-mediated disease is one or more of diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes. The present invention further provides a pharmaceutical composition, which is a formulation comprising any of the compounds described above, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, as a medicament active ingredient, together with pharma- ceutically acceptable additives. "Cancer" or "malignancy" refers to any of a number of diseases characterized by the uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or via the bloodstream and lymphatic system to other sites in the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cell" refers to a cell at an early, intermediate, or late stage that undergoes multiple stages of tumor progression. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compounds of formula I are used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer. Autoimmune diseases are caused by the body's immune response to substances or tissues that are normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutral leukopenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the present invention relate to the treatment of autoimmune diseases such as psoriasis and multiple sclerosis. Inflammatory diseases include many conditions characterized by pathological inflammation of tissues. Examples of inflammatory diseases include acne vulgaris, asthma, abdominal disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammation, reperfusion injury, rheumatoid arthritis, nodular disease, vasculitis, mite-induced airway inflammation, and interstitial cystitis. There is a clear overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, as seen in allergic reactions and some muscle diseases, and many immune system diseases cause abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

[0024] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, Ohio) naming systems. For the definition of terms used in the present invention, unless otherwise specified, the initial definition of a group or term in this specification applies to the group or term throughout the specification. For terms that are not specifically defined in this specification, the meaning that a person skilled in the art can give them based on the disclosure and context should be given.

[0025] "Substituted" means that a hydrogen atom in a molecule is replaced with another, different atom or molecule. The minimum and maximum carbon atom content in the hydrocarbon group are designated by prefixes. For example, the prefix C a~b An alkyl group refers to an alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1~4 "Alkyl group" means an alkyl group containing from 1 to 4 carbon atoms. "Alkyl group" means a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1~6 By alkyl group is meant an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more of the substituents defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl), and hexyl. The alkyl group may be part of another group, for example a C1 to C6 alkoxy group. The terms "cycloalkyl group" and "cycloalkane" refer to saturated or partially saturated cyclic groups having carbon atoms, no ring-forming heteroatoms, and a single ring or multiple rings (including fused and unfused rings). For polycyclic ring systems having aromatic and non-aromatic rings without ring-forming heteroatoms, the term "cycloalkyl group" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthylene-5-yl). The term "cycloalkyl group" includes cycloalkenyl groups such as cyclohexenyl groups. Examples of cycloalkyl groups include, for example, adamantyl groups, cyclopropyl groups, cyclobutyl groups, cyclohexyl groups, cyclopentyl groups, cyclooctyl groups, cyclopentenyl groups, and cyclohexenyl groups. Examples of cycloalkyl groups including polycyclic bicycloalkyl ring systems include bicyclohexyl groups, bicyclopentyl groups, bicyclooctyl groups, etc. For example, formula 50: TIFF2025503478000080.tif33170

[0026] The term "alkenyl group" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, in some embodiments 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and having at least one vinyl unsaturation site (>C=C<). For example, a Ca-Cb alkenyl group refers to an alkenyl group having a to b carbon atoms, and includes, for example, a vinyl group, a propenyl group, an isopropenyl group, a 1,3-butadiene group, and the like. The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl group" is meant to include hydrocarbon groups having one triple bond and one double bond. For example, a (C2-C6)alkynyl group is meant to include ethynyl, propynyl, and the like. "Halogen" is fluorine, chlorine, bromine or iodine. A "haloalkyl group" means that the hydrogen atoms in the alkyl group may be replaced with one or more halogen atoms. For example, C 1~4 Haloalkyl group refers to an alkyl group containing from 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms. The terms "heterocycle", "heterocycloalkyl group", and "heterocycloalkane" refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom, where a heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. The term "heteroaryl ring" refers to an aromatic unsaturated ring containing at least one heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom.

[0027] "Stereoisomer" includes enantiomers and diastereomers. The compounds of the present invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomers. All stereoisomers of the compounds of the present invention include, but are not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist as optically active, and have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute chiral configuration of the molecule. These stereoisomers have the same chemical structure, but different stereostructures. A particular stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and there may be no stereoselectivity or stereoorientation during the course of a chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity. For example, the C atom marked with "*" in the ring in the compound of formula 51 numbered Wee1-92 in the table of the present invention is a chiral center. TIFF2025503478000081.tif57170

[0028] The term "pharmaceutical acceptable" means that a carrier, carrier, diluent, adjuvant, and / or formed salt is usually chemically or physically compatible with the other ingredients that make up a drug dosage form and is physiologically compatible with the receptor. The pharmaceutical composition of the present invention may be any reusable pharmaceutical preparation form, such as oral, injection, or external use, and oral dosage forms include, but are not limited to, tablets, capsules, oral solutions, granules, pills, and suspensions, and injections are selected from water needles and powders, and external preparations are selected from patches and pastes. Any of the preparations can be manufactured according to a conventional pharmaceutical technique by adding a pharmacopoeia carrier as necessary, with the compound of the present invention, its stereoisomer, or pharmacopoeia acceptable salt as the pharmacopoeia active ingredient, and the pharmacopoeia active ingredient per unit dose is 0.1mg to 1000mg, for example, 0.1mg to 1000mg per tablet, preferably 5 to 500mg. The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (inner salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. They can also be obtained by mixing the above compounds or their stereoisomers with a certain amount of acid or base appropriately (e.g., equiequivalent amounts). These salts can be obtained by forming a precipitate in a solution and collecting it by filtration, by recovering it after the solvent has evaporated, or by reacting in an aqueous medium and lyophilizing it. The salts referred to in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds. In some embodiments, one or more compounds of the present invention can be used in combination with each other. Compounds of the present invention can also be used in combination with other active agents to prepare drugs or drug compositions for regulating cell function or treating disease. When a group of compounds is used, these compounds can be administered to a subject simultaneously, separately, or sequentially. Of course, according to the above content of the present invention, many other forms of modifications, substitutions, or changes can be made based on the general technical knowledge and conventional means of those skilled in the art without departing from the above basic technical idea of ​​the present invention.

[0029] The beneficial effects of the present invention are as follows: Compared with the prior art, the compounds of the present invention have superior wee1 kinase inhibitory activity and tumor cell proliferation inhibitory activity, and have lower inhibition of cytochrome P450 enzymes and hERG potassium ion channels, making them safer. The above content of the present invention will be described in more detail below with reference to specific embodiments in the form of examples. However, it should be understood that the scope of the above invention should not be limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The structure of the compound is confirmed by magnetic resonance (NMR) and mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The data are given in ppm. NMR measurements were performed on Bruker AvanceIII 400 and Bruker Avance 300 magnetic resonance spectrometers using deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard. For LC-MS measurements, a Shimadzu liquid quality analyzer (Shimadzu LC-MS 2020 (ESI)) was used. For HPLC measurements, a Shimadzu high-performance liquid chromatograph (Shimadzu LC-20A) was used. For MPLC (medium pressure preparative chromatography), a Gilsong X-281 reversed phase preparative chromatograph was used. For thin layer chromatography, Yantai Yellow Sea HSGF254 or Qingdao GF254 silicon gel plates (China), 0.4mm to 0.5mm specifications were used for separation of purified products by thin layer chromatography. For column chromatography, Yantai Yellow Sea silica gel 200 to 300 mesh silica gel (China) was generally used as the carrier.

[0031] The known starting materials of the present invention may be synthesized by methods known in the art, or may be purchased from companies such as Anergy Chemical, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, and Bailingwei Science and Technology. Reactions were carried out under a nitrogen atmosphere unless otherwise stated in the examples. Solutions were aqueous solutions unless otherwise stated in the examples. Reaction temperatures were room temperature unless otherwise stated in the examples. M is moles / liter unless otherwise stated in the examples. THF: tetrahydrofuran; DIPEA: N,N-diisopropylethylamine DCM: dichloromethane; TFA: trifluoroacetic acid; m-CPBA: meta-chloroperbenzoic acid DMF: dimethylformamide; PTSA: paratoluenesulfonamide; DMSO: dimethylsulfoxide; NBS: N-bromosuccinimide; AIBN: azodiisobutyronitrile;

[0032] Unless otherwise specified in the examples, the HPLC measurement conditions are as follows. <Method A> Column specification: Bostongreen C18 150mm*4.6mm 5um; Mobile phase: A: 0.05% TFA Water B: 0.05% TFA acetonitrile; Gradient: B from 5% to 95% in 10.0min and hold 95% for 5.0min; Flow rate: 1.5mL / min; Column temperature: 40℃. <Method B> Column specification: Bostongreen ODS 150mm*4.6mm 5um; Mobile phase: A: 0.01M NH4HCO3Water B: Acetonitrile; Gradient: B from 5% to 95% in 10.0min and hold 95% for 5.0min; Flow rate: 1.5mL / min; Column temperature: 40℃. Unless otherwise stated, the SFC splitting conditions were: column size: 3 μm, 150 mm * 3 mm; mobile phase: A: CO2; mobile phase B: ethanol; flow rate: 1 mL / min; column temperature: 40 °C.

[0033] <Intermediate Example 1: Synthesis of Intermediate IM-1> TIFF2025503478000082.tif42170 Step 1: Synthesis of compound IM-1-3: In a dry one-neck flask, the substrate IM-1-2 (8.15 g, 35 mmol) and THF (50 mL) were added, stirred and dissolved, then IM-1-1 (6.3 g, 37 mol) and DIPEA (15 mL, 75 mol) were added, heated to 110 °C, and reacted, and monitored by LC-MS. After the reaction was completed, the system was allowed to return to room temperature, and after the solid precipitated, it was filtered and dried in an oven to obtain the following: crude product IM-1-3 (9.87 g, 76.6% yield), LCMS (ESI + ) m / z: 369.2 [M+H] + . "Step 2: Synthesis of compound IM-1-4:" In a dry one-neck flask, the substrate IM-1-3 (9.16 g, 27.5 mmol) and DCM (18 mL) were added, stirred and dissolved, then TFA (18 mL) was slowly added, heated to 75 °C, and the reaction was monitored by LC-MS. After the reaction was completed, the organic solvent was concentrated under reduced pressure, dissolved in ethanol, added 6M NaOH solution, stirred at room temperature, and monitored by LC-MS. After the reaction was completed, the solid precipitated after concentration under reduced pressure. The solid was filtered, washed three times with water, washed three times with cold ethanol, and dried at room temperature to obtain the following: crude product IM-1-4 (5 g, 81.7% yield), LCMS (ESI + ) m / z: 223.1 [M+H] + . Step 3: Synthesis of compound IM-1: In a dry two-neck flask, the substrate IM-1-4 (5.20 g, 23.4 mmol), potassium carbonate (4.53 g, 32.8 mmol) and IM-1-5 (5.55 g, 25.7 mmol) were added, and the mixture was replaced with nitrogen three times. Then, cuprous iodide (4.46 g, 23.4 mmol), N,N'-dimethylethylenediamine (4.13 g, 46.8 mmol) and 1,4-dioxane (100 mL) were added, and the mixture was stirred until homogeneous. The mixture was then heated to 120°C and reacted, and the reaction was monitored by LC-MS and TLC. After the reaction was completed, aqueous ammonia was added and stirred, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, water was removed with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound IM-1 (5.1 g, 61% yield), LCMS (ESI + ) m / z: 358.1 [M+H] + .

[0034] <Intermediate Example 2: Synthesis of Intermediate IM-2> TIFF2025503478000083.tif41170 Step 1: Synthesis of compound IM-2-3: In a dry one-neck flask, the substrate IM-2-1 (7.12 g, 50 mmol) and DMSO (30 mL) were added, stirred and dissolved, then IM-2-2 (9.9 g, 50 mmol) was added, heated to 90 °C and reacted, and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product IM-2-3 (12.12 g, 76% yield), LCMS (ESI + ) m / z: 320.3 [M+H] + . Step 2: Synthesis of compound IM-2-4: In a dry one-neck flask, the substrate IM-2-3 (12.12 g, 38 mmol) and DCM (18 mL) were added, stirred and dissolved, and then TFA (18 mL) was slowly added, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum concentration to obtain a residue. Methanol (70 mL) was added to the residue, stirred and dissolved, and then polyformal (7 g) and acetic acid (1 mL) were added, stirred at room temperature for 30 min, sodium cyanoborohydride (3.8 g, 60 mmol) was added, and the reaction was carried out by heating to 50 ° C. After the reaction was completed, the reaction was cooled to room temperature, the solid was filtered, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound IM-2-4 (7.6 g, 85.8% yield), LCMS (ESI + ) m / z: 234.2 [M+H] + . Step 3: Synthesis of compound IM-2: In a dry one-neck flask, the substrate IM-2-4 (5 g, 21.5 mmol) and methanol (40 mL) were added and dissolved by stirring. Pd / C (500 mg) was then added and replaced with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the Pd / C was removed with diatomaceous earth, and the organic layer was concentrated under reduced pressure to obtain the following: product IM-2 (4.0 g, crude), LCMS (ESI + ) m / z: 204.2 [M+H] + .

[0035] <Intermediate Example 3: Synthesis of Intermediate IM-3> TIFF2025503478000084.tif51170 Step 1: Synthesis of compound IM-3: In a dry two-neck flask, the substrate IM-1-4 (138 mg, 620.88 μmol), potassium carbonate (101 mg, 620.88 μmol) and IM-3-1 (130 mg, 521.82 μmol) were added, and the mixture was replaced with nitrogen three times. Then, cuprous iodide (99 mg, 519.82 μmol), N,N'-dimethylethylenediamine (106 mg, 1.20 mmol) and 1,4-dioxane (10 mL) were added, and the mixture was stirred until homogenous. The mixture was then heated to 120°C and reacted, and monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, aqueous ammonia was added, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound IM-3 (130 mg, 53.62% yield), LCMS (E+) m / z: 391.2 [M+H] + .

[0036] <Intermediate Example 4: Synthesis of Intermediate IM-4> TIFF2025503478000085.tif46170 Step 1: Synthesis of compound IM-4: In a dry one-neck flask, the substrate IM-2-3 (1 g, 3.13 mmol) and methanol (10 mL) were added and dissolved by stirring. Pd / C (200 mg) was then added and replaced with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the Pd / C was removed with diatomaceous earth and the organic phase was concentrated under reduced pressure to obtain the following: product IM-4 (700 mg, crude), LCMS (ESI + ) m / z: 290.2 [M+H] + .

[0037] <Intermediate Example 5: Synthesis of Intermediate IM-5> TIFF2025503478000086.tif47170 Step 1: Synthesis of compound IM-5: In a one-necked reaction flask, the substrate IM-3 (0.2 g, 0.51 mmol) and anhydrous THF (5 mL) were added and dissolved by stirring. m-CPBA (208.2 g, 1.02 mmol, purity 85%) was added and stirred at room temperature for 40 minutes, and the mixture was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and then isolated by medium pressure liquid chromatography to obtain the following: IM-5 (160 mg), LCMS (ESI + ) m / z: 407.1 [M+H] + .

[0038] <Intermediate Example 6: Synthesis of Intermediate IM-6> TIFF2025503478000087.tif45170 Step 1: Synthesis of compound IM-6: In a one-necked reaction flask, the substrate IM-1 (0.2 g, 0.56 mmol) and anhydrous THF (5 mL) were added and dissolved by stirring. m-CPBA (144.9 mg, 0.84 mmol, purity 85%) was added and stirred at room temperature for 40 minutes, and the mixture was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and isolated by medium pressure liquid chromatography to obtain the following: IM-6 (150 mg, 0.40 mmol, 71.8% yield), LCMS (ESI + ) m / z: 374.1 [M+H] + .

[0039] Example 1: Synthesis of Compound 1 TIFF2025503478000088.tif47170Step 1: Synthesis of compound 1-2 In a dry round-bottom flask, 2-bromo-6-fluoropyridine (3 g, 15 mmol) and tetrahydrofuran (25 mL) were added. The temperature was lowered to -40°C, and NaHMDS (12.79 g, 85.23 mmol) was slowly added dropwise to the system. After stirring at -40°C for 30 minutes, dimethyl sulfoxide (3.21 g, 34.09 mmol) was added and stirred at this temperature for 3 hours. The reaction was quenched with water, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, and purified by MPLC to give the following: Compound 1-2 (1.5 g, 6.00 mmol), LCMS (ESI) m / z: 252.0 [M+H]+ . Step 2: Synthesis of Compounds 1-3 In a dry flask at room temperature, compound 1-2 (1.5 g, 6.00 mmol), tetrabutylammonium bromide (193.1 mg, 0.6 mmol), and dichloromethane (10 mL) were added. After stirring at room temperature for 10 minutes, sodium hydroxide (9.60 g, 239.9 mmol) and water (10 mL) were added. The reaction was stirred at room temperature for 12 hours, quenched with water, and extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to give compound 1-3 (450 mg, 1.63 mmol), LCMS (ESI) m / z: 278.0 [M+H]. + . Step 3: Synthesis of Compounds 1-4 In a dry microwave tube, substrate 1-3 (93 mg, 336.77 μmol), IM-1-4 (89.82 mg, 404.13 μmol), cuprous iodide (64.14 mg, 336.77 μmol), potassium carbonate (65.17 mg, 505.16 μmol) and N,N'-dimethylethylenediamine (29.64 mg, 336.77 μmol) were added under nitrogen protection, followed by 1,4-dioxane (5 mL). The reaction was heated at 120 °C for 10 hours under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, filtered, and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to give compound 1-4 (50 mg, 119.76 μmol), LCMS (ESI) m / z: 418.1 [M+H]. + . Step 4: Synthesis of Compound 1 Compound 1-4 (30 mg, 71.9 μmol) was dissolved in tetrahydrofuran (1 mL), metachloroperbenzoic acid (18.74 mg, 107.8 μmol) was added, and the mixture was stirred at room temperature for 1 hour. After the raw material was consumed, N,N-diisopropylethylamine (43 mg, 0.33 mmol) and 1-5 (15.3 mg, 80.1 μmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (acidic) to obtain the following: Compound 1 (30 mg, 53.51 μmol). LCMS (ESI) m / z: 561.3 [M+H] + ,HPLC Method A:R T =5.05min, purity: 98.2%. 1 H NMR(400MHz,methanol-d6)δ 8.79(s,1H),8.05-8.01(m,1H),7.93(d,J=8.4Hz,1H),7.61(d,J=7.6Hz,1H),7.57-7.42(m,2H),7.03-6.88(m,2H), 5.71-5.67(m,1H),5.06-5.05(m,1H),4.98-4.95(m,1H),4.80-4.78(m,2H),3.20-3.18(m,5H), 3.04(s,4H),2.65-2.63(m,5H), 2.36(s,4H),1.92-1.75(m,2H),1.53(d,J=2.4Hz,2H).

[0040] Example 2: Synthesis of Compound 2 TIFF2025503478000089.tif38170Step 1: Synthesis of compound 2-1: In a dry one-neck flask, the substrate IM-1 (43 mg, 120.30 μmol) and toluene (1 mL) were added, stirred and dissolved, then m-CPBA (43.60 mg, 252.64 μmol) was added, reacted at room temperature for 30 min, and monitored by LC-MS. After the reaction was completed, DIPEA (80.6 mg, 623.65 μmol, 108.63 μL) was added, stirred for 10 min, then IM-4 (45.14 mg, 0.156 mmol) was added, and monitored by LC-MS. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 2-1 (45 mg, 62.64% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.08(s,1H),8.80(s,1H),8.00(t,J=8.0Hz,1H),7.74(d,J=8.2Hz,1H),7.59(d,J=7.7Hz,1H),7.51 (s,2H),6.61(d,J=8.5Hz,2H),5.71-5.61(m,1H),5.31(s,1H),4.99(dd,J=10.2,1.5Hz,1H),4.83(d d,J=17.1,1.5Hz,1H),4.68(d,J=5.9Hz,2H),4.49(s,1H),4.42(d,J=23.5Hz,1H),3.55(t,J=10.6Hz ,1H),3.27-3.20(m,2H),2.96(t,J=9.0Hz,1H),1.93(s,2H),1.46(s,6H),1.39(s,5H),1.32(s,4H). 1H NMR(400MHz,DMSO-d6,D2O)δ 8.81(s,1H),8.02(t,J=7.9Hz,1H),7.73(d,J=7.8Hz,1H),7.60(d,J=7.7Hz,1H),7 .51(s,2H),6.62(d,J=8.5Hz,2H),5.71-5.61(m,1H),5.04-5.01(m,1H),4.85-4.81 (m,1H),4.69(d,J=5.9Hz,2H),4.49-4.41(m,2H),3.57(t,J=9.0Hz,1H),3.36-3.25 (m,2H),2.96(t,J=8.4Hz,1H),1.94(s,2H),1.47(s,6H),1.39(s,5H),1.32(s,4H). LCMS(E+)m / z:599.4 [M+H] +, HPLC method B:R T =8.23min, purity: 91.5%. Step 2: Synthesis of compound 2: In a dry one-neck flask, substrate 2-1 (40.00 mg, 66.81 μmol) and DCM (3 mL) were added, stirred and dissolved, then TFA (3 mL) was slowly added, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum concentration to obtain a residue, which was purified by medium pressure liquid chromatography (acid method) to obtain the following: Compound 2 (25 mg, 61.08% yield). 1 H NMR(400MHz, methanol-d4)δ 8.77(s,1H),7.97(t,J=7.9Hz,1H),7.76(d,J=8.1Hz,1H),7.63(dd,J=7.8,0.8Hz,1H),7 .54(d,J=8.4Hz,2H),6.67(d,J=8.6Hz,2H),5.70(m,1H),5.03(dq,J=10.2,1.2Hz,1H),4. 92(d,J=1.2Hz,1H),4.80(d,J=6.1Hz,2H),4.66(s,1H),4.48(s,1H),3.76(dd,J=10.6,2. 5Hz,1H),3.42-3.34(m,3H),2.32(d,J=11.1Hz,1H),2.05(d,J=11.3Hz,1H),1.57(s,6H). LCMS(E+)m / z:499.2 [M+H] +, HPLC Method A:R T=5.03min, purity: 99.2%.

[0041] <Example 3: Synthesis of Compound 3> TIFF2025503478000090.tif46170Step 1: Synthesis of compound 3: In a dry one-neck flask, the substrate IM-1 (3.57 g, 10 mmol) and tetrahydrofuran (30 mL) were added, stirred and dissolved, and then m-CPBA (2.5 g, 15 mmol, purity 85%) was added and reacted at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (6.45 g, 50 mmol) was added, stirred for 10 min, and then IM-2 (2.1 g, 10 mmol) was added and monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum concentration, and the remaining impurities were purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 3 (2.1 g, 41% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.04(s,1H),8.79(s,1H),8.00(t,J=7.9Hz,1H),7.75(s,1H),7.59(d,J=7.7Hz,1H),7.48(s,2H) ,6.56(d,J=8.5Hz,2H),5.71-5.61(m,1H),5.32(s,1H),4.99(dd,J=10.3,1.5Hz,1H),4.82(d,J=1 7.1,1H),4.67(d,J=6.0Hz,2H),4.27(s,1H),3.42(s,1H),3.13(d,J=9.0Hz,1H),2.78(d,J=9.5,1 H),2.52(d,J=9.7Hz,2H),2.25(s,3H),1.87(d,J=9.3Hz,1H),1.76(d,J=9.2Hz,1H),1.46(s,6H). 1H NMR(400MHz,DMSO-d6,D2O)δ 8.80(s,1H),8.02(t,J=7.9Hz,1H),7.73(s,1H),7.61(d,J=7.8Hz,1H),7.48(s,2H),6.58(d,J= 8.6Hz,2H),5.71-5.60(d,J=10.3Hz,1H),5.03(m,1H),4.83(d,J=17.1Hz,1H),4.68(d,J=5.9Hz, 2H),4.29(s,1H),3.49(s,1H),3.35(d,J=9.5Hz,1H),3.17(d,J=9.4Hz,1H),2.82(d,J=9.7Hz,1H ),2.56(d,J=9.7Hz,1H),2.27(s,3H),1.91(d,J=9.6Hz,1H),1.81(d,J=9.6Hz,1H),1.47(s,6H). LCMS(E+)m / z:513.2 [M+H] +, HPLC method B:R T =6.02min, Purity:98.4%.

[0042] <Example 4: Synthesis of Compound 4> TIFF2025503478000091.tif38170 Step 1: Synthesis of compound 4-3: In a dry one-neck flask, substrate 4-1 (114 mg, 910.78 μmol) and methanol (2 mL) were added, stirred and dissolved, then NaBH4 (38 mg, 1.00 mmol) was added, and the reaction was carried out at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, dilute hydrochloric acid was slowly added in an ice bath to quench the reaction, and the solvent was removed by vacuum concentration. DMSO (4 mL) was added to the residue, stirred and dissolved, then potassium tert-butoxide (337 mg, 2.36 mmol) was added, and compound 4-2 (141 mg, 999.29 μmol) was added, and the reaction was heated to 80 ° C. and monitored by LC-MS. After the reaction was completed, the mixture was extracted three times with ethyl acetate, and the organic phase was concentrated under reduced pressure, and the mixture was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 4-3 (99 mg, 50.71% yield), LCMS (ESI + ) m / z: 249.2 [M+H] + . Step 2: Synthesis of compound 4-4: In a dry one-neck flask, the substrate 4-3 (99 mg, 398.75 μmol) and ethanol (4 mL) were added and dissolved by stirring. Then, Fe (67 mg, 1.20 mmol) and CH3COOH (47.89 mg, 797.50 μmol, 45.65 μL) were added and the reaction was heated to 80 °C and monitored by LC-MS. After the reaction was completed, it was filtered through diatomaceous earth, washed with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the following: crude product 4-4 (80 mg, crude), LCMS (ESI + ) m / z: 219.2 [M+H] + . Step 3: Synthesis of compound 4: In a dry one-neck flask, the substrate IM-1 (71 mg, 0.2 mmol) and toluene (2 mL) were added, stirred and dissolved, and then m-CPBA (52 mg, 0.3 mmol, purity 85%) was added, and the reaction was carried out at room temperature for 1 h, and the reaction was monitored by LC-MS. After the reaction was completed, DIPEA (83.58 mg, 646.69 μmol, 112.64 μL) was added, and after stirring for 10 min, compound 4-4 (52.39 mg, 0.24 mmol) was added, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum concentration to obtain the residue, which was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 4 (8 mg, 6.32% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),8.84(s,1H),8.04(t,J=7.9Hz,1H),7.73(d,J=7.2,1H),7.62-7.60(m,3H),6.9 0(d,J=7.7Hz,2H),5.71-5.62(m,1H),5.33(s,1H),4.99(dd,J=10.3,1.4Hz,1H),4.82(dd,J= 10.3,1.4Hz,1H),4.68(d,J=5.9Hz,2H),4.44-4.42(m,1H),2.77-2.60(m,6H),2.04-2.03(m, 1H),1.84-1.81(m,1H),1.66-1.63(m,1H),1.57-1.54(m,1H),1.46(s,6H),1.36-1.33(m,1H). 1H NMR(400MHz,DMSO-d6,D2O)δ 8.85(s,1H),8.04(t,J=7.9Hz,1H),7.72(d,J=7.6Hz,1H),7.64-7.59(m,3H),6. 92(d,J=8.5Hz,2H),5.72-5.62(m,1H),5.03(d,J=10.3Hz,1H),4.83(d,J=17.1Hz ,1H),4.69(d,J=5.9Hz,2H),4.49(s,1H),2.81-2.63(m,6H),2.06(s,1H),1.86( s,1H),1.70-1.68(m,1H),1.62(d,J=7.4Hz,1H),1.47(s,6H),1.42-1.37(m,1H). LCMS(E+)m / z:528.2 [M+H] +, HPLC method B:R T =6.34min, purity:82.9%.

[0043] <Example 5: Synthesis of Compound 5> TIFF2025503478000092.tif42170 Step 1: Synthesis of compound 5: In a dry one-neck flask, the substrate IM-3 (30 mg, 77 μmol) and tetrahydrofuran (2 mL) were added, stirred and dissolved, then m-CPBA (20 mg, 116 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (50 mg, 385 μmol) was added, stirred for 10 min, and then compound IM-2 (20 mg, 98.39 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 5 (15 mg, 55.87% yield). 1H NMR(400MHz,DMSO-d6)δ 10.01(s,1H),8.77(s,1H),7.76(t,J=8.0Hz,1H),7.50(s,2H),7.30(d,J=7.9Hz,1H),6 .59-6.55(m,3H),5.68-5.58(m,1H),5.00(d,J=10.1Hz,1H),4.89(d,J=17.0Hz,1H),4.7 4(s,2H),4.26(s,1H),3.40(s,1H),3.37(s,6H),3.30(s,1H),3.13(d,J=9.0Hz,1H),2. 78-2.76(m,1H),2.47(s,1H),2.24(s,3H),1.85(d,J=9.3Hz,1H),1.75(d,J=9.1Hz,1H). 1 H NMR (400 MHz, DMSO-d 6, D2O)δ 8.79(s,1H),7.80(t,J=7.9Hz,1H),7.50-7.48(m,2H),7.30(d,J=7.8Hz,1H),6.64(d,J=8.0Hz ,1H),6.58(d,J=8.7Hz,2H),5.69-5.59(m,1H),5.05-5.03(m,1H),4.92-4.87(m,1H),4.74(s, 2H),4.27(s,1H),3.44(s,1H),3.36(s,6H),3.35-3.32(m,1H),3.16(d,J=9.4Hz,1H),2.79(d, J=9.7Hz,1H),2.48(d,J=9.9Hz,1H),2.24(s,3H),1.89(d,J=9.5Hz,1H),1.78(d,J=9.4Hz,1H). LCMS(E+)m / z:546.3 [M+H] + ,HPLC Method B:R T =5.56min, purity: 92%.

[0044] <Example 6: Synthesis of Compound 6> TIFF2025503478000093.tif39170 Project 1: Synthesis of Compound 6-1: In a dry one-neck flask, substrate 4-1 (1 g, 6.2 mmol) and ethanol / water (10:1, 20 mL) were added, stirred and dissolved, and then p-nitrobenzaldehyde (1 g, 6.6 mmol) and sodium hydroxide (620 mg, 15.5 mmol) were added, and the reaction was carried out at room temperature and monitored by LC-MS. After the reaction was completed, the precipitated solid was filtered, washed three times with a small amount of ethanol, and air-dried to obtain the following: compound 6-1 (1 g, 63% yield), LCMS (E+) m / z: 259.2 [M+H] + . Step 2: Synthesis of compound 6-2: In a dry one-neck flask, the substrate 6-1 (103 mg, 0.4 mmol) and methanol (5 mL) were added and dissolved by stirring. Pd / C (15 mg) was then added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the Pd / C was removed by diatomaceous earth filtration, and the organic phase was concentrated under reduced pressure to obtain the following: crude product 6-2 (80 mg, crude), LCMS (ESI + ) m / z: 231.2 [M+H] + . Step 3: Synthesis of compound 6: In a dry one-neck flask, the substrate IM-3 (30 mg, 77 μmol) and tetrahydrofuran (2 mL) were added, stirred and dissolved, then m-CPBA (20 mg, 116 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (50 mg, 385 μmol) was added, stirred for 10 min, then compound 6-2 (20 mg, 86.84 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 6 (5 mg, 17.74% yield). 1H NMR (400 MHz, DMSO-d6)δ 10.18(s,1H),8.85(s,1H),7.78(t,J=7.9Hz,1H),7.61(d,J=8.1Hz,2H),7.30(d ,J=7.9Hz,1H),7.20(d,J=8.4Hz,2H),6.61(d,J=7.9Hz,1H),5.69-5.60(m,1H), 5.02-4.99(m,1H),4.90(dd,J=17.1,1.7Hz,1H),4.74(d,J=6.0Hz,2H),3.37(s, 6H),2.99-2.86(m,4H),2.76-2.69(m,3H),2.33-2.29(m,2H),1.92-1.88(m,3H). 1 H NMR (400 MHz, DMSO-d 6, D2O)δ 8.86(s,1H),7.83(t,J=7.9Hz,1H),7.60(d,J=8.0Hz,2H),7.31(d,J=7.8Hz ,1H),7.22(d,J=8.2Hz,2H),6.68(d,J=8.0Hz,1H),5.70-5.61(m,1H),5.07 -5.04(m,1H),4.90(d,J=17.2Hz,1H),4.75(d,J=5.9Hz,2H),3.36(s,6H),3 .09-2.85(m,4H),2.79-2.72(m,3H),2.38-2.32(m,2H),1.91-1.89(m,3H). LCMS (E+) m / z: 573.6 [M+H] + ,HPLC Method B:R T =5.05min, purity: 87.7%.

[0045] <Example 7: Synthesis of Compound 7> TIFF2025503478000094.tif45170 Project 1: Synthesis of Compound 7: In a dry one-neck flask, the substrate IM-3 (30 mg, 77 μmol) and tetrahydrofuran (2 mL) were added, stirred and dissolved, and then m-CPBA (20 mg, 116 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (50 mg, 385 μmol) was added, stirred for 10 min, and then compound 4-4 (20 mg, 91.62 μmol) was added, and monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum concentration, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 7 (5 mg, 19.08% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),δ 8.82(s,1H),7.79(t,J=8.0Hz,1H),7.61(s,2H),7.28(d,J=7.8Hz,1H),6.89(d,J=9.0Hz ,2H),6.60(d,J=8.1Hz,1H),5.69-5.59(m,1H),5.02-4.99(m,1H),4.89(d,J=17.2Hz,1H) ,4.74(s,2H),4.41(d,J=7.8Hz,1H),3.18(s,3H),3.16(s,3H),2.79-2.70(m,6H),2.03- 2.02(m,1H),1.91-1.80(m,1H),1.67-1.63(m,1H),1.57-1.54(m,1H),1.38-1.33(m,1H). 1 H NMR (400MHz, DMSO-d 6, D2O)δ 8.83(s,1H),7.82(t,J=8.0Hz,1H),7.60(s,2H),7.29(d,J=7.8Hz,1H),6.92 (d,J=8.8Hz,2H),6.66(d,J=8.0Hz,1H),5.68-5.62(m,1H),5.05(d,J=10.4H z,1H),4.89(d,J=16.9Hz,1H),4.75(s,2H),4.48(s,1H),3.36(s,6H),2.78- 2.72(m,6H),2.05(s,1H),1.84(s,1H),1.70-1.59(m,2H),1.40-1.33(m,1H). LCMS(E+)m / z:561.5 [M+H] + ,HPLC Method B:R T=5.10min, purity:90.2%.

[0046] <Example 8: Synthesis of Compound 8> TIFF2025503478000095.tif65170 Step 1: Synthesis of compound 8-2: In a dry one-neck flask, the substrate 4-2 (1 g, 7.09 mmol), compound 8-1 (1.70 g, 8.50 mmol) and potassium carbonate (2.45 g, 17.72 mmol) were added, dissolved in DMF (10 mL), heated to 90 ° C, reacted for 1 h, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step reaction without purification to obtain the following: compound 8-2 (2.1 g, crude), yellow oil. LCMS (E +) m / z: 322.4 [M + H] + . Step 2: Synthesis of compound 8-3: In a dry one-neck flask, the substrate 8-2 (2.1 g, 6.53 mmol) was added, dissolved in HCl / 1,4-dioxane (10 mL), and reacted at room temperature for 1 h, and monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted with saturated sodium carbonate solution and ethyl acetate three times, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step reaction without purification to obtain the following: compound 8-3 (1.3 g, crude), yellow oil. LCMS (E+) m / z: 222.4 [M+H] + . Step 3: Synthesis of compound 8-4: In a dry one-neck flask, the substrate 8-3 (700 mg, 3.16 mmol) and compound 4-1 (396.00 mg, 3.16 mmol) were added, dissolved in MeOH / AcOH (10 mL), and reacted at room temperature for 1 h, and monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted three times with water and ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the remaining impurities were removed by MPLC to obtain compound 8-4 (300 mg, 907.93 μmol, 28.70% yield), a yellow solid. LCMS (E+) m / z: 331.4 [M+H] + . Step 4: Synthesis of compound 8-5: In a dry one-neck flask, substrate 8-4 (300 mg, 907.93 μmol) and formaldehyde (136.31 mg, 4.54 mmol) were added, dissolved in MeOH / AcOH (8 mL), heated to 50 °C, reacted for 3 h, then NaCNBH3 (142.64 mg, 2.27 mmol) was added to the system, heated to 70 °C, reacted overnight, and monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure, extracted three times with water and ethyl acetate, combined the organic phase, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated the organic solvent under reduced pressure, and removed the remaining impurities by MPLC to obtain compound 8-5 (283 mg, 739.44 μmol, 81.44% yield), yellow solid. LCMS (E+) m / z: 345.5 [M+H] + . Step 5: Synthesis of compound 8-6: In a dry one-neck flask, the substrate 8-5 (1.5 g, 4.74 mmol) was added, dissolved in MeOH / AcOH (10 mL), Pd / C (172.73 mg, 1.42 mmol) was added, and the mixture was replaced with H2 three times. The reaction was carried out at room temperature for 3 h and monitored by LC-MS. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was used in the next step without purification to obtain the following: compound 8-6 (1.5 g, crude), black oil. LCMS (E+) m / z: 315.5 [M+H] + . Step 6: Synthesis of compound 8: In a dry one-neck flask, the substrate 8-6 (50 mg, 159.00 μmol) and compound IM-5 (64.63 mg, 159.00 μmol) were added, dissolved in THF (3 mL), and then PTSA (54.76 mg, 318.00 μmol) was added. The mixture was heated to 110 °C and stirred for 5 h. The mixture was monitored by LC-MS. After the reaction was completed, the organic solvent was concentrated under reduced pressure, extracted three times with water and ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining impurities were removed by MPLC to obtain compound 8 (23 mg, 35.02 μmol, 22.02% yield), a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.79(s,1H),7.56(s,2H),7.30(d,J=7.9Hz,1H),6.91(d,J=8.6H z,2H),6.59(d,J=8.2Hz,1H),5.68-5.59(m,1H),5.00(d,J=10.1Hz,1H),4.89(d,J=17.0Hz,1 H),4.74(s,2H),3.74-3.66(m,2H),3.37(s,6H),2.94-2.91(m,1H),2.79-2.57(m,9H),2.06( s,3H),1.97-1.93(m,1H),1.75-1.53(m,6H),1.42(d,J=11.1Hz,1H),1.24(d,J=11.7Hz,1H). LCMS(ESI+)m / z:657.4 [M+H] + ,HPLC Method B:R T =5.54min, purity:98.9%.

[0047] <Example 9: Synthesis of Compound 9> TIFF2025503478000096.tif36170Step 1: Synthesis of compound 9-2: In a dry one-neck flask, substrate 4-1 (161 mg, 1 mmol) was added in ethanol / water (10:1, 10 mL), and after stirring, 9-1 (186 mg, 1.1 mmol) and sodium hydroxide (100 mg, 2.5 mmol) were added, and the reaction was carried out at room temperature and monitored by LC-MS. After the reaction was completed, the precipitated solid was filtered, washed three times with a small amount of ethanol, and dried to obtain the following: compound 9-2 (150 mg, 50% yield), LCMS (E+) m / z: 303.1 [M+H] + . Step 2: Synthesis of compound 9-3: In a dry one-neck flask, the substrate 9-2 (81 mg, 0.27 mmol) and methanol (5 mL) were added and dissolved by stirring. Pd / C (15 mg) was then added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the Pd / C was removed with diatomaceous earth and the organic phase was concentrated by distillation under reduced pressure to obtain the following: product 9-3 (42 mg, crude), LCMS (ESI + ) m / z: 275.2 [M+H] + . Step 3: Synthesis of compound 9: In a dry one-neck flask, the substrate IM-3 (40 mg, 110.71 μmol) and THF (2 mL) were added, stirred and dissolved, then m-CPBA (29 mg, 116 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (75.12 mg, 581.26 μmol) was added, stirred for 10 min, and then compound 9-3 (36.45 mg, 132.85 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 9 (35 mg, 51.26% yield). 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.82(s,1H),7.77-7.75(m,1H),7.59(s,1H),7.45(d,J=8.9Hz,1H),7.29(d,J=7 .4Hz,1H),6.89(d,J=8.8Hz,1H),6.58(d,J=8.0Hz,1H),5.67-5.60(m,1H),5.00(d,J=10.2Hz, 1H),4.88(d,J=17.1Hz,1H),4.74(s,2H),4.01(q,J=7.0Hz,2H),3.37(s,6H),3.06-3.03(m,2H ),2.85-2.84(m,1H),2.71-2.64(m,4H),2.28(s,1H),1.95-1.87(m,4H),1.32(t,J=6.9Hz,3H). 1 H NMR(400MHz,DMSO-d6,D2O)δ 8.82(s,1H),7.81-7.77(m,1H),7.58(s,1H),7.45(d,J=8.7Hz,1H),7.29(d,J=7.9Hz,1H), 6.90(d,J=8.9Hz,1H),6.61(d,J=8.1Hz,1H),5.67-5.60(m,1H),5.02(d,J=10.2Hz,1H),4. 88(d,J=17.1Hz,1H),4.73(s,1H),4.01(q,J=7.0Hz,2H),3.36(s,6H),3.03(d,J=14.9Hz,2 H),2.86(s,1H),2.71-2.65(m,4H),2.29(s,1H),1.96-1.87(m,4H),1.32(t,J=6.9Hz,3H). LCMS(E+)m / z:617.2 [M+H] + ,HPLC Method B:R T =6.66min, purity: 95.4%.

[0048] <Example 10: Synthesis of Compound 10> TIFF2025503478000097.tif31170 Project 1: Synthesis of Compound 10-1: In a dry one-neck flask, substrate 4-1 (1 g, 6.2 mmol) and ethanol / water (10:1, 20 mL) were added, stirred and dissolved, and then meta-nitrobenzaldehyde (1 g, 6.6 mmol) and sodium hydroxide (620 mg, 15.5 mmol) were added, and the reaction was carried out at room temperature and monitored by LC-MS. After the reaction was completed, the precipitated solid was filtered, washed three times with a small amount of ethanol, and air-dried to obtain the following: compound 10-1 (1 g, 63% yield), LCMS (E+) m / z: 259.2 [M+H] + . Step 2: Synthesis of compound 10-2: In a dry one-neck flask, substrate 10-1 (103 mg, 0.4 mmol) and methanol (5 mL) were added and dissolved by stirring. Pd / C (15 mg) was then added and replaced with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth and the organic phase was concentrated by distillation under reduced pressure to obtain the following: product 10-2 (65 mg, crude), LCMS (ESI + ) m / z: 231.2 [M+H] + . Step 3: Synthesis of compound 10: In a dry one-neck flask, the substrate IM-3 (40 mg, 110.71 μmol) and THF (2 mL) were added, stirred and dissolved, then m-CPBA (29 mg, 116 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (85.85 mg, 664.24 μmol) was added, stirred for 10 min, and then compound 10-2 (30.6 mg, 132.85 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 10 (15 mg, 22.22% yield). 1H NMR(400MHz,DMSO-d6)δ 10.22(s,1H),8.87(s,1H),7.83(t,J=7.9Hz,1H),7.76(s,1H),7.47(d,J=8.2Hz,1H),7.31(d ,J=7.8Hz,1H),7.21(t,J=7.8Hz,1H),6.95(d,J=7.6Hz,1H),6.61(d,J=8.1Hz,1H),5.69-5.6 0(m,1H),5.01(d,J=10.1Hz,1H),4.89(d,J=17.0Hz,1H),4.74(d,J=6.0Hz,2H),3.41(s,6H)3 .03-2.98(m,2H),2.89-2.86(m,1H),2.78-2.71(m,4H),2.32-2.31(m,1H),1.97-1.89(m,4H). 1 H NMR (400 MHz, DMSO-d 6, D2O)δ 8.87(s,1H),7.84(t,J=7.9Hz,1H),7.74(s,1H),7.47(d,J=8.2Hz,1H),7.31(d,J=7.7Hz,1H ),7.23(t,J=7.8Hz,1H),6.96(d,J=7.7Hz,1H),6.64(d,J=8.0Hz,1H),5.70-5.60(m,1H),5.0 3(d,J=10.2Hz,1H),4.89(d,J=17.0Hz,1H),4.74(d,J=6.0Hz,2H),3.36(d,J=2.1Hz,6H),3. 03-2.98(m,2H),2.93-2.86(m,1H),2.78-2.69(m,4H),2.33-2.32(m,1H),1.99-1.84(m,4H). LCMS(E+)m / z:573.1 [M+H] + ,HPLC Method B:R T =6.24min, purity: 93.9%.

[0049] <Example 11: Synthesis of Compound 11> TIFF2025503478000098.tif64170 Project 1: Synthesis of Compound 11-2: In a dry one-neck flask, the substrate 4-2 (2 g, 14.17 mmol), compound 11-1 (3.17 g, 17.01 mmol) and potassium carbonate (4.89 g, 35.44 mmol) were added, dissolved in DMF (10 mL), heated to 90 °C, reacted for 1 h, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step reaction without purification to obtain: compound 11-2 (4 g, crude), yellow solid. LCMS (E+) m / z: 308.3 [M+H] + . Step 2: Synthesis of compound 11-3: In a dry one-neck flask, the substrate 11-2 (4 g, 13.01 mmol) was added and dissolved in HCl / 1,4-dioxane (10 mL), and reacted at room temperature for 1 h, and monitored by LC-MS. After completion of the reaction, the organic phase was concentrated under reduced pressure, extracted with saturated sodium carbonate and ethyl acetate three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step reaction without purification to obtain: compound 11-3 (2.5 g, crude), yellow solid. LCMS (E+) m / z: 208.2 [M+H] + . Step 3: Synthesis of compound 11-4: In a dry one-neck flask, the substrate 11-3 (1 g, 4.83 mmol) and the free base of compound 4-1 (724.81 mg, 5.79 mmol) were added, dissolved in MeOH / AcOH (10 mL), and reacted at room temperature for 1 h, and monitored by LC-MS. After completion of the reaction, the organic phase was concentrated under reduced pressure, extracted three times with saturated sodium carbonate and ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the remaining impurities were removed by MPLC to give compound 11-4 (1.5 g, 4.27 mmol, 88.42% yield), a yellow solid. LCMS (E+) m / z: 317.4 [M+H] + . Step 4: Synthesis of compound 11-5: In a dry one-neck flask, the substrate 11-4 (1.5 g, 4.74 mmol) and Pd / C (172.73 mg, 1.42 mmol) were added, dissolved in MeOH / AcOH (10 mL), purged with H2 three times, and reacted with H2 at room temperature for 3 h and monitored by LC-MS. After completion of the reaction, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step reaction without purification to obtain the following: compound 11-5 (1.5 g, crude), black oil. LCMS (E+) m / z: 287.4 [M+H] + . Step 5: Synthesis of compound 11: In a dry one-neck flask, the substrate 11-5 (35 mg, 122.20 μmol) and compound IM-5 (49.67 mg, 122.20 μmol) were added, dissolved in THF (3 mL), and then PTSA (52.61 mg, 305.50 μmol) was added. The mixture was heated to 110 °C and stirred for 5 h. The mixture was monitored by LC-MS. After the reaction was completed, the organic solvent was concentrated under reduced pressure, extracted three times with water and ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining impurities were removed by MPLC to obtain compound 11 (21 mg, 32.56 μmol, 26.65% yield), a green solid. 1 H NMR(600MHz,DMSO-d6)δ 10.13(s,1H),8.80(s,1H),7.80(s,1H),7.59(s,2H),7.30(d,J=7.7Hz,1H),6.91(d,J=8.5Hz,2 H),6.59(d,J=7.9Hz,1H),5.64(ddt,J=18.3,13.6,6.4Hz,1H),5.00(d,J=10.1Hz,1H),4.90(d,J =17.0Hz,1H),4.75(s,2H),3.37(s,6H),3.13-3.09(m,6H),2.98-2.91(m,2H),2.80-2.63(m,4H) ,2.63-2.55(m,2H),2.03-2.00(m,2H),1.77-1.60(m,2H),1.43-1.39(m,1H),1.29-1.25(m,1H). LCMS(ESI + ) m / z: 629.5 [M+H] + ,HPLC Method B:R T=5.94min,purity:97.5%

[0050] <Example 12: Synthesis of compound 12> TIFF2025503478000099.tif33170Step 1: Synthesis of compound 12-2: In a dry one-neck flask, the substrate IM-2-1 (416 mg, 2.1 mmol) and DMSO (8 mL) were added and stirred to dissolve, then potassium carbonate (387 mg, 2 mmol) and compound 12-1 (310 mg, 2 mmol) were added, and the reaction was heated to 90 ° C. and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, water was added, and the reaction was stirred until a solid precipitated. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 12-2 (200 mg, 30% yield), LCMS (ESI + ) m / z: 334.2 [M+H] + . Step 2: Synthesis of compound 12-3: In a dry one-neck flask, substrate 12-2 (200 mg, 0.6 mmol) and DCM (5 mL) were added, stirred and dissolved, then TFA (5 mL) was slowly added, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (5 mL) was added to the residue, stirred and dissolved, then polyformal (180 mg) and acetic acid (500 μL) were added, stirred at room temperature for 30 min, sodium cyanoborohydride (75 mg, 1.2 mmol) was added, and the reaction was heated to 50 °C and monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, the solid was filtered, the organic phase was concentrated under reduced pressure, and the mixture was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 12-3 (120 mg, 81% yield), LCMS (ESI + ) m / z: 248.2 [M+H] + . Step 3: Synthesis of compound 12-4: In a dry one-neck flask, substrate 12-3 (120 mg, 0.48 mmol) and methanol (5 mL) were added and dissolved by stirring. Pd / C (12 mg) was then added and replaced with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth and the organic phase was concentrated by vacuum distillation to obtain the following: product 12-4 (90 mg, 86.4% yield). LCMS (ESI + ) m / z: 218.2 [M+H] + . Step 4: Synthesis of compound 12: In a dry one-neck flask, the substrate IM-1 (52 mg, 0.15 mmol) and THF (3 mL) were added, stirred and dissolved, and then m-CPBA (121 mg, 0.6 mmol, purity 85%) was added and reacted at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (98 mg, 758.28 μmol) was added, stirred for 10 min, and then 12-4 (33 mg, 151.86 μmol) was added and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 12 (13 mg, 15.38% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.09(s,1H),8.82(s,1H),8.00-7.98(m,1H),7.78(d,J=8.1Hz,1H),7.61(d,J=7.7Hz,2H),7.28(dd ,J=8.8,2.6Hz,1H),6.74(d,J=8.7Hz,1H),5.69-5.63(m,1H),5.32(s,1H),4.99(dd,J=10.3,1.5Hz, 1H),4.82(d,J=17.1Hz,1H),4.68(d,J=6.0Hz,2H),3.97(s,1H),3.39(s,1H),3.25-3.21(m,2H),2.8 0-2.74(m,2H),2.32(s,3H),2.22(s,3H),1.83(d,J=9.3Hz,1H),1.72(d,J=9.2Hz,1H),1.46(s,6H). 1 H NMR (600MHz, DMSO-d 6,D2O)δ 8.82(s,1H),8.03-8.01(m,1H),7.76(d,J=8.1Hz,1H),7.65-7.57(m,2H),7.29(dd,J=8.7 ,2.7Hz,1H),6.76(d,J=8.7Hz,1H),5.70-5.63(m,1H),5.03-5.01(m,1H),4.82(d,J=17.1 Hz,1H),4.69(d,J=5.8Hz,2H),3.98(s,1H),3.42(s,1H),3.27-3.23(m,2H),2.81-2.74(m ,2H),2.31(s,3H),2.23(s,3H),1.86(d,J=9.5Hz,1H),1.75(d,J=9.4Hz,1H),1.47(s,6H). LCMS(E+)m / z:527.3 [M+H] + ,HPLC Method B:R T =6.53min, purity: 94.6%.

[0051] <Example 13: Synthesis of compound 13> TIFF2025503478000100.tif41170 Step 1: Synthesis of compound 13-2: In a dry one-neck flask, the substrate 13-1 (1.03 g, 10 mmol) and DMSO (15 mL) were added, stirred and dissolved, then potassium carbonate (2 g, 14 mmol) and p-fluoronitrobenzene (1.43 g, 10 mmol) were added, heated to 100 °C, and reacted and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, the solid was filtered, and the filtrate was concentrated and purified by medium pressure liquid chromatography (acid method) to obtain the following: compound 13-2 (2 g, 89% yield), LCMS (ESI + ) m / z: 225.1 [M+H] + . Step 2: Synthesis of compound 13-3: In a dry one-neck flask, substrate 13-2 (44 mg, 0.2 mmol) and THF (2 mL) were added and stirred to dissolve, then HATU (84 mg, 0.22 mmol) and DIPEA (28 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 30 min. Then, methylamine hydrochloride (67 mg, 1 mmol) was added, and the mixture was heated to 65°C for reaction, and monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the following: crude product 13-3 (24 mg, crude), LCMS (ESI + ) m / z: 238.3 [M+H] + . Step 3: Synthesis of compound 13-4: In a dry one-neck flask, the substrate 13-3 (24 mg, 0.1 mmol) and methanol (4 mL) were added and dissolved by stirring. Pd / C (5 mg) was then added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the Pd / C was removed by diatomaceous earth filtration, and the organic phase was concentrated by vacuum distillation to obtain the following: crude product 13-4 (18 mg, crude), LCMS (ESI + ) m / z: 208.2 [M+H] + . Step 4: Synthesis of compound 13: In a dry one-neck flask, the substrate IM-1 (31 mg, 86 μmol) and THF (2 mL) were added, stirred and dissolved, then m-CPBA (26 mg, 129 μmol) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (55 mg, 425 μmol) was added, stirred for 10 min, then 13-4 (18 mg, 85 μmol) was added, and the reaction was carried out by heating to 80 ° C. and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 13 (7 mg, 16% yield). 1H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),7.97-4.95(m,1H),7.75(d,J=4.4Hz,2H),7.60(d,J=7.6H z,1H),7.49(s,2H),6.59(d,J=8.0Hz,2H),5.69-5.62(m,1H),5.33(s,1H),5.04-4.9 5(m,1H),4.98(d,J=10.0Hz,1H),4.82(d,J=17.0Hz,1H),4.67(d,J=5.9Hz,2H),3.78 (s,2H),3.41-3.40(m,2H),2.60(d,J=4.7Hz,3H),1.46(s,6H),1.08(t,J=7.0Hz,3H). 1 H NMR (600 MHz, DMSO-d 6, D2O)δ 8.80(s,1H),8.00-7.97(m,1H),7.82(d,J=4.4Hz,1H),7.72(s,1H),7.61(d ,J=7.6Hz,1H),7.49(s,1H),6.59(d,J=8.2Hz,2H),5.69-5.63(m,1H),5.02 (d,J=10.2Hz,1H),4.83(d,J=17.0Hz,1H),4.68(s,2H),3.81(s,2H),3.42( q,J=7.0Hz,2H),2.62(d,J=4.6Hz,3H),1.47(s,6H),1.08(t,J=7.0Hz,3H). LCMS (E+) m / z: 517.3 [M+H] + ,HPLC Method B:R T =6.25min, purity: 90.5%.

[0052] <Example 14: Synthesis of Compound 14> TIFF2025503478000101.tif34170 Project 1: Synthesis of Compound 14-1: In a dry one-neck flask, the substrate 13-2 (44 mg, 0.2 mmol) and THF (2 mL) were added and dissolved by stirring. Then, HATU (84 mg, 0.22 mmol) and DIPEA (28 mg, 0.22 mmol) were added and stirred at room temperature for 30 min. N-methylpiperazine (40 mg, 0.4 mmol) was added and the reaction was heated to 65 °C and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the following: crude product 14-1 (50 mg, crude), LCMS (ESI + ) m / z: 307.2 [M+H] + . Step 2: Synthesis of compound 14-2: In a dry one-neck flask, substrate 14-1 (50 mg, 0.16 mmol) and methanol (4 mL) were added and dissolved by stirring, then Pd / C (5 mg) was added, and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain the following: product 14-2 (40 mg, crude), LCMS (ESI + ) m / z: 277.2 [M+H] + . Step 3: Synthesis of compound 14: In a dry one-neck flask, the substrate IM-1 (38 mg, 106 μmol) and THF (2 mL) were added, stirred and dissolved, then m-CPBA (40 mg, 200 μmol) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (65 mg, 500 μmol) was added, stirred for 10 min, and then compound 14-2 (40 mg, crude) was added, and the reaction was carried out by heating to 80 ° C. and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 14 (12.2 mg, 17.58% yield). 1H NMR(600MHz, methanol-d4)δ 8.76(s,1H),7.96-7.93(m,1H),7.76(s,1H),7.62(d,J=7.7Hz,1H),7.43(d,J=8.4 Hz,2H),6.68(d,J=8.6Hz,2H),5.73-5.67(m,1H),5.03(d,J=10.2Hz,1H),4.91(d,J =10.2Hz,1H),4.80(d,J=5.8Hz,2H),4.59(s,2H),4.23(s,2H),3.76(s,2H),3.44(q ,J=7.0Hz,2H),2.90-2.85(m,4H),2.62(s,3H),1.57(s,6H),1.18(t,J=7.0Hz,3H). LCMS(E+)m / z:586.4 [M+H] + ,HPLC Method B:R T =6.23min, purity: 91.9%.

[0053] <Example 15: Synthesis of Compound 15> TIFF2025503478000102.tif61170 Step 1: Synthesis of compound 15-2: In a one-necked reaction flask, substrate 15-1 (2.44 g, 12.50 mmol), NBS (3.33 g, 18.70 mmol), and AIBN (0.2 g, 1.21 mmol) were added and dissolved in CCl4 (20 mL). After purging with nitrogen three times, the reaction flask was stirred overnight at 85 °C in an oil bath under nitrogen protection and monitored by TLC. The solvent was removed by concentration under reduced pressure, and the crude product was used directly in the next step reaction without purification to obtain crude product 15-2 (3 g, 11.03 mmol, 88.1% yield). Step 2: Synthesis of compound 15-3: 4-Amino-1-methylpiperidine (1.8 g, 15.77 mmol) was added to the crude 15-2 (3 g, 11.03 mmol) and dissolved. The reaction was then heated to 40° C. and stirred for 2 h. The reaction was monitored by LC-MS until completion. The reaction was isolated by column chromatography to give the following: compound 15-3 (1.3 g, 4.72 mmol, 42.86% yield), LCMS (ESI + ) m / z: 276.1 [M+H] + . Step 3: Synthesis of compound 15-4: In a reaction flask, substrate 15-3 (0.6 g, 1.70 mmol) was added, dissolved in anhydrous methanol (10 mL), and Pd / C (10% wt.) (60 mg) was added. After replacing with hydrogen gas three times, the mixture was stirred at room temperature overnight and monitored by LC-MS. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure, and then isolated and purified by column chromatography to obtain the following: compound 15-4 (474 ​​mg, 1.92 mmol, 88.7% yield), LCMS (ESI + ) m / z: 246.2 [M+H] + . Step 4: Synthesis of compound 15: In a microwave reaction tube, substrate IM-5 (39.3 mg, 0.097 mmol), substrate 15-4 (47.43 mg, 0.19 mmol), anhydrous acetonitrile (4 mL), and TFA (55.18 mg, 0.48 mmol) were added. The reaction was carried out in a microwave at 90°C for 4 hours and monitored by LC-MS. After the reaction was completed, it was quenched with saturated NaHCO3 solution, extracted with ethyl acetate three times, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The following was obtained by medium pressure liquid chromatography purification: product 15 (10 mg, 0.017 mmol, 17.6% yield). 1 H NMR (600MHz, Chloroform-d6) δ 8.89(s,1H),8.03(s,1H),7.79(d,J=8.3Hz,1H),7.75(s,1H),7.71-7.68(m,1 H),7.56(d,J=8.2Hz,1H),7.31(d,J=7.7Hz,1H),6.74(d,J=8.0Hz,1H),5.69-5 .63(m,1H),5.05-4.96(m,2H),4.92(d,J=6.3Hz,2H),4.37(s,3H),3.34(s,6H) ),3.11(s,2H),2.44(s,3H),2.33(s,2H),2.05(s,2H),1.89(d,J=12.5Hz,2H). LCMS(ESI + ) m / z: 588.1 [M+H] + ,HPLC Method B:R T =5.34min,purity:96.5%

[0054] <Example 16: Synthesis of compound 16> TIFF2025503478000103.tif90170 Step 1: Synthesis of compound 16-2: In a dry one-neck flask, pyridine (7.91 g, 100 mmol) and acetonitrile (40 mL) were added and stirred until homogenous. 2-Chloroacetamide (9.35 g, 100 mmol) was added and the mixture was heated to 90° C. and reacted overnight. After the reaction was completed, it was cooled to room temperature, and the solid was filtered, washed with petroleum ether three times, and recrystallized with ethanol to obtain the following: Product 16-2 (10.8 g, 62% yield). Step 2: Synthesis of compound 16-4: In a dry one-neck flask, substrate 16-2 (3.6 g, 21.15 mmol) and n-butanol (50 mL) were added and stirred until homogenous. 16-3 (1.82 g, 7.05 mmol), acetic acid (1.5 mL) and piperidine (2.5 mL) were added and the reaction was heated to 120 °C and monitored by LC-MS. After completion of the reaction, the solid was filtered, the filtrate was extracted three times with CHCl3 (containing 5% MeOH), the organic phase was concentrated under reduced pressure, and the obtained solid was recrystallized with methanol to give the following: product 16-4 (1.92 g, 91% yield), LCMS (ESI + ) m / z: 298.2 [M+H] + . Step 3: Synthesis of compound 16-5: In a dry one-neck flask, substrate 16-4 (500 mg, 1.68 mmol) and methanol (15 mL) were added and stirred until homogenous. Pd / C (50 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give product 16-5 (310 mg, 69% yield), LCMS (ESI + ) m / z: 268.1 [M+H] + . Step 4: Synthesis of compound 16: In a dry one-neck flask, the substrate IM-1 (70 mg, 200 μmol) and tetrahydrofuran (4 mL) were added, stirred and dissolved, and then m-CPBA (60 mg, 300 μmol, purity 85%) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (129.24 mg, 1.00 mmol) was added, and after stirring for 10 min, 16-5 (53.47 mg, 200.00 μmol) was added, and the reaction was carried out at 80 ° C. in a microwave oven and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 16 (6.3 mg, 5.22% yield). 1 H NMR (600MHz, DMSO-d6) δ 11.81(s,1H),10.43(s,1H),8.93(s,1H),8.08-8.05(m,1H),7.81-7.78(m,3H), 7.64(d,J=7.7Hz,1H),7.58(d,J=8.2Hz,2H),6.22(s,1H),5.71-5.65(m,1H),5. 35(s,1H),5.01(d,J=10.2Hz,1H),4.84(d,J=17.2Hz,1H),4.69(d,J=5.9Hz,2H) ,3.47(s,2H),3.09(s,1H),3.00(s,2H),1.84(s,2H),1.56(s,2H),1.47(s,6H). 1 H NMR(600MHz,DMSO-d6,D2O)δ 8.93(s,1H),8.09-8.06(m,1H),7.81-7.76(m,3H),7.65(d,J=7.6Hz,1H)7.59(d,J=8.4Hz,2H),6.27(s,1H),5.71-5.64(m,1H),5.04(d,J= 10.2Hz,1H),4.84(d,J=17.1Hz,1H),4.70(d,J=5.8Hz,2H),3.93(s,2H),3.16(s,1H),3.02(s,2H),1.88(s,2H),1.57(s,2H),1.48(s,6H). LCMS(E+)m / z:577.3 [M+H] + ,HPLC Method B:R T =5.96min, purity: 95.5%.

[0055] <Example 17: Synthesis of compound 17> TIFF2025503478000104.tif35170Step 1: Synthesis of compound 17-3 In a dry round-bottom flask, 17-2 (130 mg, 0.88 mmol), DIPEA (0.58 g, 4.4 mmol) were dissolved in DMSO (1 mL), and then 17-1 (1.1 mmol, 148 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was monitored by LC-MS, diluted with water, extracted with ethyl acetate three times, washed with saturated saline, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and directly used in the next step without purification to obtain the following crude product 17-3 (150 mg, 0.64 mmol, 65.6% yield), LCMS (ESI+) m / z: 235.1 [M+H]+. Step 2: Synthesis of compound 17-4 In a 50 mL round-bottom flask, 17-3 (150 mg, 0.64 mmol), catalytic amount of Pd / C (45 mg) and MeOH (3 mL) were added, purged with hydrogen gas three times, and stirred vigorously under hydrogen atmosphere at room temperature for 12 h. Monitored by LC-MS, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by medium pressure liquid chromatography to give compound 17-4 (100 mg, 0.49 mmol, 76.1% yield), LCMS (ESI+) m / z: 205.1 [M+H]+. Step 3: Synthesis of compound 17 m-CPBA (39 mg, 0.18 mmol) was added to a solution of IM-1 (51 mg, 0.18 mmol) in THF (1 mL) and stirred at room temperature for 10 minutes. After monitoring by LC-MS and TLC, DIPEA (122 mg, 0.75 mmol) was added and stirred at room temperature for 20 minutes. Then, 17-4 (51 mg, 0.15 mmol) was added and stirred at room temperature for 1 hour. After monitoring by LC-MS, water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by acidic preparative high performance liquid chromatography to obtain the following: Compound 17 (26 mg, 0.05 mmol, 35.5% yield). 1H NMR(600MHz,DMSO-d6)δ 10.13(s,1H),8.81(s,1H),8.04(s,1H),7.74(d,J=7.6Hz,1H),7.60(d,J= 7.7Hz,1H),7.57(s,1H),6.82(d,J=8.5Hz,2H),5.69-5.64(m,1H),5.32(s, 1H),4.99(d,J=10.2Hz,1H),4.82(d,J=17.1Hz,1H),4.68(s,2H),4.42(s,2 H),2.82-2.72(m,2H),1.84(s,4H),1.49(s,1H),1.46(s,6H),1.38(s,2H). LCMS(E+)m / z:514.5[M+H] + ,HPLC Method A:R T =7.13min, Purity:>99.9%.

[0056] <Example 18: Synthesis of compound 18> TIFF2025503478000105.tif63170 Step 1: Synthesis of compound 18-2 In a dry one-neck flask, 18-1 (4 g, 20 mmol) was added, dissolved in DCM (50 mL), and TFA (25 mL) was added at room temperature, stirred for 30 minutes, and monitored by LC-MS. After completion of the reaction, the solvent was removed in vacuum, diluted with water, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain crude product 18-2, which was used in the next step without purification (1.8 g, crude). LCMS (ESI+) m / z: 100.1 [M+H] + Step 2: Synthesis of compound 18-4 In a dry one-neck flask, 18-2 (1 g, 7 mmol) was dissolved in DMSO (10 mL), and 18-3 (1 g, 10.5 mmol) and K2CO3 (4.8 g, 35 mmol) were added in sequence. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was monitored by LC-MS, diluted with 100 mL water, extracted with ethyl acetate three times, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 18-4, which was used in the next step without purification (1.35 g, crude). LCMS (ESI+) m / z: 221.1 [M+H]+ Step 3: Synthesis of compound 18-6 In a dry round-bottom flask, 18-4 (1.35 g, 6.2 mmol) and 18-5 (1.47 g, 7.4 mmol) were dissolved in methanol (15 mL), and acetic acid (1 mL) was added, and the mixture was reacted at room temperature for 30 minutes. Then, sodium cyanoborohydride (584 mg, 9.3 mmol) was added, and the mixture was heated to 60 ° C and stirred for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the following: crude product 18-6 (1.75 g, crude), LCMS (ESI +) m / z: 403.2 [M + H] + Step 4: Synthesis of compound 18-7 In a 50 mL round-bottom flask, 18-6 (1.75 g, 4.4 mmol), catalytic amount of Pd / C (200 mg) and MeOH (20 mL) were added. The mixture was stirred at room temperature for 12 h under hydrogen atmosphere. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography to give compound 18-7 (1.46 g, 3.9 mmol, 90.2% yield). LCMS (ESI+) m / z: 373.3 [M+H] + . Step 5: Synthesis of compound 18-8 In a dry round-bottom flask, 18-7 (1.46 g, 3.9 mmol) was dissolved in THF and slowly added with 2 M LiAlH4 in tetrahydrofuran (10 mL, 20 mmol) at 0 °C under N2 protection. The reaction temperature was raised to 65 °C and stirred at this temperature for 6 h and monitored by LC-MS. After completion of the reaction, the reaction temperature was lowered to 0 °C and water (0.76 mL), 10% aqueous NaOH (0.76 mL), and quenched with water (2.3 mL). Stirred at room temperature for 30 min, dried over anhydrous Na2SO4, and filtered through diatomaceous earth. The filtrate was concentrated in vacuum and purified by column chromatography to give compound 18-8 (736 mg, 2.5 mmol, 65.6% yield). LCMS (ESI+) m / z: 287.2 [M+H] + . Step 6: Synthesis of compound 18 According to the synthesis method of step 3 in Example 17, except that 18-8 (42.1 mg, 0.15 mmol) was used instead of 17-4 (51 mg, 0.15 mmol) in step 3, the same synthesis method was used to obtain the following: compound 18 (20 mg, 33.6 μmol, 22.9% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.19(s,1H),8.84(s,1H),8.04(s,1H),7.76(d,J=8.1Hz,1H),7.62(d,J=7.7Hz,3H), 7.00(d,J=8.5Hz,3H),5.70-5.63(m,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.2Hz,1 H),4.68(s,3H),4.45(s,1H),3.82(s,6H),3.37(s,2H),2.92(s,3H),2.69(t,J=12.4H z,2H),2.23(d,J=64.4Hz,2H),2.07(d,J=11.8Hz,1H),1.78-1.63(m,2H),1.47(s,6H). LCMS(ESI+)m / z:596.4 [M+H] + . HPLC Method A:R T =6.35min,purity:96.9%

[0057] <Example 19: Synthesis of Compound 19> TIFF2025503478000106.tif38170 Step 1: Synthesis of compound 19-2: In a dry one-neck flask, substrate 19-1 (200 mg, 0.1 mmol) and DMSO (5 mL) were added, and while stirring, potassium carbonate (470 mg, 3.4 mmol) and p-fluoronitrobenzene (141 mg, 1 mmol) were added, and the temperature was raised to 110 ° C. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, iodomethane (141 mg, 1 mmol) was added, and the temperature was raised to 90 ° C. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, the solid was filtered, and the filtrate was concentrated and purified by medium pressure liquid chromatography (base method) to obtain the following: product 19-2 (50 mg, 19% yield), LCMS (ESI+ ) m / z: 262.3 [M+H] + . Step 2: Synthesis of compound 19-3: In a dry one-neck flask, substrate 19-2 (50 mg, 0.19 mmol) and methanol (2 mL) were added and dissolved by stirring. Pd / C (10 mg) was then added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth and the organic phase was concentrated by distillation under reduced pressure to obtain the following: product 19-3 (40 mg, crude), LCMS (ESI + ) m / z: 232.2 [M+H] + . Step 3: Synthesis of compound 19: In a dry one-neck flask, the substrate IM-1 (52 mg, 0.15 mmol) and tetrahydrofuran (3 mL) were added, stirred and dissolved, and then m-CPBA (121 mg, 0.6 mmol, purity 85%) was added and reacted at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (95.17 mg, 736.42 μmol) was added, stirred for 10 min, and then 19-3 (40 mg, crude) was added and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 19 (35 mg, 40.96% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.99-7.96(m,1H),7.75(s,1H),7.62(d,J=7.7Hz,1H),7.4 7(s,2H),6.62(d,J=8.3Hz,2H),6.19(d,J=23.4Hz,1H),5.69-5.63(m,1H),4.99(d,J=1 0.2Hz,1H),4.83(d,J=17.1Hz,1H),4.67(s,2H),3.89(s,2H),3.51(s,2H),3.29(s,3H) ,2.97(s,3H),2.22(s,2H),2.00(d,J=7.8Hz,2H),1.76(d,J=14.1Hz,1H),1.46(s,6H). 1H NMR (600MHz, DMSO-d6, DO) δ 8.81(s,1H),8.01-7.98(m,1H),7.74(s,1H),7.62(d,J=7.8Hz,1H),7.49(s,2 H),6.64(d,J=8.4Hz,2H),5.69-5.63(m,1H),5.02(d,J=10.2Hz,1H),4.83(d,J =17.0Hz,1H),4.68(s,2H),3.90-3.88(m,2H),3.43-3.42(m,4H),3.14-3.12( m,1H),2.97(s,3H),2.23-2.20(m,2H),2.03(s,2H),1.82(s,1H),1.47(s,6H). LCMS(E+)m / z:541.3 [M+H] + ,HPLC Method B:R T =5.65min, Purity: 93.2%.

[0058] <Example 20: Synthesis of Compound 20> TIFF2025503478000107.tif44170 Step 1: Synthesis of compound 20-2: In a dry one-neck flask, substrate 20-1 (136 mg, 1 mmol) and DMSO (8 mL) were added and dissolved by stirring. Then, potassium carbonate (332 mg, 2.4 mmol) and p-fluoronitrobenzene (141 mg, 1 mmol) were added and the reaction was heated to 90°C and monitored by LC-MS. After the reaction was completed, the reaction was cooled to room temperature, water was added, and the mixture was stirred to precipitate a solid. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 20-2 (180 mg, 81.8% yield), LCMS (ESI + ) m / z: 221.2 [M+H] + . Step 2: Synthesis of compound 20-3: In a dry one-neck flask, substrate 20-2 (180 mg, 0.82 mmol) and methanol (7 mL) were added, and Pd / C (18 mg) was added while stirring. The mixture was purged with hydrogen gas five times, and the reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain the following: crude product 20-3 (120 mg, crude), LCMS (ESI+) m / z: 191.1 [M+H]+. Step 3: Synthesis of compound 20: In a dry one-neck flask, the substrate IM-1 (52 mg, 0.15 mmol) and tetrahydrofuran (3 mL) were added, stirred and dissolved, and then m-CPBA (121 mg, 0.6 mmol, purity 85%) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (98 mg, 758.28 μmol) was added, and after stirring for 10 min, compound 20-3 (46 mg, 151.86 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 20 (25 mg, 0.05 mmol, 33.84% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.07(s,1H),8.80(s,1H),8.02-8.01(m,1H),7.75(s,1H),7.60(d,J=7.6Hz,1H),7.53-7.38(m,2 H),6.62(d,J=7.2Hz,2H),5.70-5.63(m,1H),5.33(s,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.1 Hz,1H),4.69(s,2H),4.60(s,1H),4.53(s,1H),3.75(d,J=6.8Hz,1H),3.67(d,J=7.4Hz,1H),3.50 (d,J=9.0Hz,1H),2.95(d,J=9.0Hz,1H),1.93(d,J=9.2Hz,1H),1.84(d,J=8.8Hz,1H),1.47(s,6H). 1H NMR(600MHz,DMSO-d6,D2O)δ 8.82(s,1H),8.05-8.02(m,1H),7.74(s,1H),7.62(d,J=7.6Hz,1H),7.52(s,2H),6.63(d, J=7.6Hz,2H),5.70-5.64(m,1H),5.03(d,J=10.2Hz,1H),4.84(d,J=17.0Hz,1H),4.70(s, 2H),4.62(s,1H),4.51(s,1H),3.78(d,J=7.4Hz,1H),3.68(d,J=7.6Hz,1H),3.52(d,J=9. 4Hz,1H),2.96(d,J=9.2Hz,1H),1.95(d,J=9.0Hz,1H),1.86(d,J=9.0Hz,1H),1.48(s,6H). LCMS(E+)m / z:500.1 [M+H] + ,HPLC Method B:R T =6.69min, Purity: 99.6%.

[0059] <Example 21: Synthesis of Compound 21> TIFF2025503478000108.tif64170 Step 1: Synthesis of compound 21-3: In a dry one-neck flask, substrate 21-1 (3.0 g, 19.34 mmol) and DMSO (20 mL) were added and dissolved by stirring. Then, potassium carbonate (2.67 g, 19.34 mmol) and 21-2 (3.82 g, 19.34 mmol) were added and heated to 100 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. A solid precipitated. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 21-3 (6 g, 18.00 mmol, 93.06% yield), LCMS (ESI + ) m / z: 334.4 [M+H] + . Step 2: Synthesis of compound 21-4: In a dry one-neck flask, substrate 21-3 (6.67 g, 20.01 mmol), TFA (2.28 g, 20.01 mmol) and DCM (50 mL) were added, stirred and dissolved, and reacted at room temperature for 18 hours, and monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the following: crude product 21-4 (4 g, crude), LCMS (ESI + ) m / z: 234.3 [M+H] + . Step 3: Synthesis of compound 21-6: In a dry one-neck flask, the substrate 21-4 (3 g, 12.86 mmol), compound 21-5 (1.46 g, 12.86 mmol), NaBH3CN (1.2 g, 19.11 mmol) and methanol (30 mL) were added, stirred and dissolved, then heated to 60 °C and reacted for 18 hours, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to obtain the following: crude product 21-6 (3 g, 9.08 mmol, 70.60% yield), LCMS (ESI + ) m / z: 331.4 [M+H] + . Step 4: Synthesis of compound 21-7: In a dry one-neck flask, substrate 21-6 (200 mg, 0.61 mmol) and methanol (10 mL) were added and stirred until homogenous. Pd / C (40 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give product 21-7 (50 mg, 27.5% yield), LCMS (ESI + ) m / z: 301 [M+H] + . Step 5: Synthesis of compound 21: In a dry one-neck flask, the substrate IM-1 (17.8 mg, 50.08 μmol) and tetrahydrofuran (2 mL) were added, stirred and dissolved, and then m-CPBA (12.9 mg, 74.74 μmol) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (6.47 mg, 50.08 μmol, 8.72 μL) was added, and after stirring for 10 min, compound 21-7 (15.05 mg, 50.08 μmol) was added, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 21 (5 mg, 8.16 μmol, 16.29% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.09(s,1H),8.82(s,1H),7.99-7.97(m,1H),7.78(d,J=7.8Hz,1H),7.60(d,J=7.8Hz,1H),7.57(s,1H),7.29-7.27(m,1 H),6.72(d,J=9.0Hz,1H),5.69-5.63(m,1H),5.33(s,1H),4.99(d,J=10.2Hz,1H),4.82(d,J=17.4Hz,1H),4.68(d,J=5.9 Hz,2H),3.95(s,1H),3.66(s,1H),3.20(q,J=8.4Hz,2H),3.02(d,J=8.4Hz,1H),2.68(d,J=7.8Hz,2H),2.56(d,J=9.0Hz, 1H),2.22(s,3H),2.16(s,1H),2.12(s,3H),1.91(s,1H),1.88(s,1H),1.74-1.69(m,4H),1.46(s,6H),1.38-1.25(m,2H). LCMS(ESI + ) m / z: 610.6 [M+H] + .HPLC Method A:R T =4.45min, purity: 99.5%.

[0060] <Example 22: Synthesis of Compound 22> TIFF2025503478000109.tif69170 Step 1: Synthesis of compound 22-2: In a dry one-neck flask, substrate 22-1 (158 mg, 499.31 μmol), TFA (3 mL) and DCM (3 mL) were added, stirred and dissolved, and reacted at room temperature for 18 hours and monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the following: crude product 22-2 (100 mg, crude), LCMS (ESI + ) m / z: 217.3 [M+H] + . Step 2: Synthesis of compound 22-3: In a dry one-neck flask, substrate 22-2 (100 mg, 462.28 μmol) and DMSO (4 mL) were added and dissolved by stirring. Then, potassium carbonate (97 mg, 701.88 μmol) and compound 4-2 (72 mg, 510.28 μmol) were added and heated to 100° C. for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was stirred. A solid precipitated. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 22-3 (150 mg, 444.56 μmol, 96.17% yield), LCMS (ESI + ) m / z: 338.4 [M+H] + . Step 3: Synthesis of compound 22-4: In a dry one-neck flask, substrate 22-3 (50 mg, 148.19 μmol) and methanol (4 mL) were added and stirred until homogenous. Pd / C (8 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give product 22-4 (20 mg, 65.06 μmol, 43.90% yield), LCMS (ESI + ) m / z: 308.4 [M+H] + . Step 4: Synthesis of compound 22: In a dry one-neck flask, substrate 22-4 (24.70 mg, 80.34 μmol) and tetrahydrofuran (2 mL) were added and stirred to dissolve, and DIPEA (51.91 mg, 401.68 μmol, 69.96 μL) and compound IM-6 (30 mg, 80.34 μmol) were added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography to obtain the following: compound 22 (5 mg, 7.30 μmol, 9.09% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.10(s,1H),8.80(s,1H),8.02(s,1H),7.79-7.78(m,1H),7.61-7.55(m,3H),7.18-7.17(m,5H), 6.77(d,J=8.4Hz,2H),5.70-5.63(m,1H),5.33(s,1H),5.00(d,J=10.3Hz,1H),4.83(d,J=17.2Hz,1 H),4.68(s,2H),3.59(d,J=11.3Hz,2H),3.38(s,2H)3.08(d,J=11.3Hz,2H),2.87(d,J=10.6Hz,2H) ,2.26(d,J=10.7Hz,2H),2.09(s,2H),1.70(d,J=12.2Hz,1H),1.60(d,J=12.1Hz,1H),1.47(s,6H). 1 H NMR (600MHz, DMSO-d 6, D2O)δ 8.81(s,1H),8.03(s,1H),7.78(s,1H),7.61-7.58(m,3H),7.18(s,5H),6.78(d,J=8 .6Hz,2H),5.69-5.63(m,1H),5.02(d,J=10.3Hz,1H),4.83(d,J=17.1Hz,1H),4.68( s,2H),3.64(s,2H),3.39(s,2H),3.08(d,J=10.9Hz,2H),2.87(d,J=10.8Hz,2H),2. 28(s,2H),2.10(s,2H),1.70(d,J=11.9Hz,1H),1.60(d,J=12.2Hz,1H),1.47(s,6H). LCMS(E+)m / z:617.4 [M+H] + ,HPLC Method B:R T =6.01min, purity:90.1%.

[0061] <Example 23: Synthesis of Compound 23> TIFF2025503478000110.tif63170 Step 1: Synthesis of compound 23-1: In a dry one-neck flask, substrate 22-1 (200 mg, 632.04 μmol) and methanol (5 mL) were added and stirred until homogenous. Pd / C (20 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to obtain the following: product 23-1 (140 mg, crude), LCMS (ESI + ) m / z: 227.3 [M+H] + . Step 2: Synthesis of compound 23-2: In a dry one-neck flask, substrate 23-1 (128.31 mg, 566.97 μmol) and DMSO (3 mL) were added and dissolved by stirring. Then, potassium carbonate (96.74 mg, 0.7 mmol) and p-fluoronitrobenzene (4-2, 80 mg, 566.97 μmol) were added and heated to 90°C for 6 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was stirred. A solid precipitated. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 23-2 (120 mg, crude), LCMS (ESI + ) m / z: 348.4 [M+H] + . Step 3: Synthesis of compound 23-3: In a dry one-neck flask, substrate 23-2 (69 mg, 198.61 μmol), TFA (3 mL) and DCM (3 mL) were added, stirred and dissolved, and reacted at room temperature for 18 hours and monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the following: crude product 23-3 (49 mg, crude), LCMS (ESI + ) m / z: 248.3 [M+H] + . Step 4: Synthesis of compound 23-4: In a dry one-neck flask, add substrate 23-3 (49.46 mg, 0.2 mmol), add methanol (4 mL), stir to dissolve, then add formaldehyde (34.06 mg, 1.00 mmol) and acetic acid (11 mL), stir for 10 minutes, add NaCNBH3 (25.14 mg, 400.00 μmol), warm to 50 °C, react for 2 hours, and monitor by LC-MS. After completion of the reaction, concentrate under reduced pressure, add water and ethyl acetate, extract three times, combine the organic phase, wash with saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain: The crude product was purified by medium pressure liquid chromatography to obtain: Compound 23-4 (30 mg, 114.80 μmol, 57.40% yield), LCMS (ESI + ) m / z: 262.3 [M+H] + . Step 5: Synthesis of compound 23-5: In a dry one-neck flask, substrate 23-4 (30 mg, 114.80 μmol) and methanol (3 mL) were added and stirred until homogenous. Pd / C (8 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give the following: product 23-5 (20 mg, crude), LCMS (ESI + ) m / z: 232.3 [M+H] + . Step 6: Synthesis of compound 23: In a dry one-neck flask, substrate 23-5 (18.58 mg, 80.34 μmol) and tetrahydrofuran (2 mL) were added and stirred to dissolve, and DIPEA (51.91 mg, 401.68 μmol, 69.96 μL) and compound IM-6 (30 mg, 80.34 μmol) were added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography to obtain the following: compound 23 (8 mg, 13.58 μmol, 16.91% yield). 1H NMR(600MHz,DMSO-d6)δ 10.09(s,1H),8.80(s,1H),8.04(s,1H),7.76(d,J=8.0Hz,1H),7.61-7.56(m,3H),6.73 (d,J=8.6Hz,2H),5.65-5.63(m,1H),5.33(s,1H),4.99(dd,J=10.3,1.6Hz,1H),4.83(dd ,J=17.1,1.7Hz,1H),4.68(d,J=6.1Hz,2H),3.57(d,J=11.2Hz,2H),3.46(s,3H),3.00( dd,J=11.3,4.8Hz,2H),2.88(s,2H),2.17-2.09(m,4H),1.66-1.54(m,2H),1.46(s,6H). 1 H NMR(600MHz,DMSO-d6,D2O)δ 8.80(s,1H),8.05(s,1H),7.76(s,1H),7.62-7.55(m,3H),6.75(s,2H),5.67-5.63(m,1H),5.02-5.01(m,1H),4.84-4.82(m,1H), 4.68(d,J=6.1Hz,2H),3.71(s,3H),3.58(d,J=11.4Hz,2H),2.99-2.89(m,4H),2.12-2.04(m,4H),1.66-1.57(m,2H),1.47(s,6H). LCMS(E+)m / z:541.3 [M+H] + ,HPLC Method B:R T =5.29min, purity: 94.1%.

[0062] <Example 24: Synthesis of Compound 24> TIFF2025503478000111.tif98170 Project 1: Synthesis of Compound 24-2: In a dry one-neck flask, substrate 24-1 (2 g, 10.25 mmol) and carbon tetrachloride (40 mL) were added and stirred until homogenous. NBS (2.74 g, 15.37 mmol) and AIBN (269.24 mg, 1.64 mmol) were added and purged with nitrogen five times. The mixture was heated to 70°C and stirred under reflux for 12 hours and monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography to give 24-2 (1.3 g, 4.74 mmol, 46.3% yield), LCMS (ESI + ) m / z: 274.1 [M+H] + . Step 2: Synthesis of compound 24-4: In a dry one-neck flask, substrates 24-2 (200 mg, 0.73 mmol) and 24-3 (166.42 mg, 1.46 mmol) were added, and the mixture was heated to 50° C. and stirred under reflux for 1 h, followed by monitoring by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure, a small amount of ethyl acetate was added, the solid was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography to give: 24-4 (180 mg, 0.65 mmol, 89.67% yield), LCMS (ESI + ) m / z: 276.1 [M+H] + . Step 3: Synthesis of compound 24-5: In a dry one-neck flask, substrate 24-4 (180 mg, 0.65 mmol) and methanol (3 mL) were added and stirred until homogenous. Pd / C (36 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to obtain the following: product 24-5 (100 mg, crude), LCMS (ESI + ) m / z: 246.3 [M+H] + . Step 4: Synthesis of compound 24-6: In a one-necked reaction flask, the substrate IM-3 (0.2 g, 0.51 mmol) and anhydrous THF (5 mL) were added and dissolved by stirring. m-CPBA (208.2 g, 1.02 mmol, purity 85%) was added and stirred at room temperature for 40 minutes, and the mixture was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and isolated by medium pressure liquid chromatography to obtain the following: compound 24-6 (130 mg, 0.31 mmol, 60.0% yield), LCMS (ESI + ) m / z: 423.5 [M+H] + . Step 5: Synthesis of compound 24: In a dry microwave tube, substrate 24-6 (31 mg, 73.38 μmol), 24-5 (36.00 mg, 146.75 μmol), TsOH (50.48 mg, 293.50 μmol) and anhydrous ACN (0.3 mL) were added and dissolved by stirring, then the tube was sealed and heated to 110 ° C in a microwave for 4 hours, and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate three times, combined the organic phase, washed with saturated saline, dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by medium pressure liquid chromatography to obtain the following: product 24 (1.5 mg, 2.55 μmol, 3.48% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.52(s,1H),8.91(s,1H),8.46(s,1H),7.95(s,1H),7.77(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.3Hz,1H), 7.40(d,J=7.9Hz,1H),6.64(d,J=8.0Hz,1H),5.66(ddt,J=16.4,10.2,6.0Hz,1H),5.02(dd,J=10.3,1.6H z,1H),4.90(dd,J=17.1,1.6Hz,1H),4.80(s,2H),4.42(s,2H),4.08-3.97(m,1H),3.38(s,6H),2.89(d,J =11.1Hz,2H),2.22(s,3H),2.07(t,J=11.8Hz,2H),1.82(dd,J=12.1,3.8Hz,2H),1.71(d,J=13.3Hz,2H). LCMS(ESI +) m / z: 588.1 [M+H] + ,HPLC Method B:R T =5.22min,purity:92.3%

[0063] <Example 25: Synthesis of Compound 25> TIFF2025503478000112.tif71170 Step 1: Synthesis of compound 25-2: In a dry one-neck flask, substrate 25-1 (0.5 g, 2.36 mmol) and DMSO (10 mL) were added and dissolved by stirring. Then, potassium carbonate (651.05 mg, 4.71 mmol) and p-fluoronitrobenzene (4-2, 332.33 mg, 2.36 mmol) were added and heated to 100 °C for 6 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. A solid precipitated. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 25-2 (0.7 g, 2.10 mmol, 89.15% yield), LCMS (ESI + ) m / z: 333.4 [M+H] + . Step 2: Synthesis of compound 25-3: In a dry one-neck flask, substrate 25-2 (0.5 g, 1.50 mmol) and methanol (10 mL) were added and stirred until homogenous. Pd / C (910 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give product 25-3 (0.4 g, 1.32 mmol, 87.91% yield), LCMS (ESI + ) m / z: 304.2 [M+H] + . Step 3: Synthesis of compound 25-4: In a dry one-neck flask, substrate 25-3 (150 mg, 0.5 mmol) and THF (4 mL) were added and dissolved by stirring. LiAlH4 (112.57 mg, 2.97 mmol) was then added and heated to 65 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred to precipitate a solid. The solid was filtered, washed three times with water, washed three times with a small amount of methanol, and dried by heating to obtain the following: product 25-4 (80 mg, 0.36 mmol, 74.46% yield), LCMS (ESI + ) m / z: 218.3 [M+H] + . Step 4: Synthesis of compound 25: In a dry one-neck flask, the substrate IM-1 (21.70 mg, 99.88 μmol) and tetrahydrofuran (2 mL) were added, stirred and dissolved, and then m-CPBA (25.86 mg, 149.82 μmol) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (64.54 mg, 499.40 μmol, 86.98 μL) was added, and after stirring for 10 min, 25-4 (21.70 mg, 99.88 μmol) was added, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: Compound 25 (9 mg, 16.06 μmol, 16.08% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.07(s,1H),8.80(s,1H),8.03-8.01(m,1H),7.75(s,1H),7.60(d,J=7.8Hz,1H),7 .51(s,2H),6.80(d,J=8.4Hz,2H),5.70-5.99(m,1H),5.31(s,1H),5.00-4.98(m,1H) ),4.84-4.81(m,1H),4.68(d,J=6.0Hz,2H),4.20(s,2H),2.47-2.44(m,2H),2.30-2 .28(m,2H),2.06(s,3H),1.88(d,J=6.6Hz,2H),1.83(d,J=6.0Hz,2H),1.46(s,6H). LCMS(ESI + ) m / z: 527.3 [M+H] + .HPLC Method B:RT :7.83min,purity:94.0%.

[0064] <Example 26: Synthesis of Compound 26> TIFF2025503478000113.tif74170 Step 1, synthesis of compound 26-3: Substrate 26-1 (1.27 g, 12.72 mmol), 26-2 (2 g, 8.48 mmol), t-BuONa (1 g, 10.17 mmol) and toluene (15 mL) were added to a dry microwave tube, stirred and dissolved, then oxygen was removed with N2 for 10 min, Pd2(dba)3 (778 mg, 0.85 mmol) and BINAP (264.6 mg, 0.43 mmol) were added, oxygen was removed with N2 for 10 min, the tube was sealed, and the reaction was heated to 110 °C in an oil bath for 12 hours and monitored by LC-MS. After the reaction was completed, it was cooled to room temperature and filtered through diatomaceous earth. The filtrate was distilled under reduced pressure and isolated by medium pressure liquid chromatography to obtain the following: product 26-3 (1.57 g, 6.15 mmol, 72.58% yield), LCMS (ESI + ) m / z: 255.2 [M+H] + . Step 2, synthesis of compound 26-5: In a dry one-neck flask, the substrate 26-3 (650 mg, 2.55 mmol) was added and dissolved in acetone (6 mL) and water (7 mL). 26-4 (637.87 mg, 3.82 mmol), Pd(OAc)2 (57.25 mg, 0.25 mmol) and sodium carbonate (542 mg, 2.55 mmol) were added, and the mixture was flushed with nitrogen three times. The reaction was heated to 50 °C under nitrogen protection for 12 h and monitored by LC-MS. After completion of the reaction, it was cooled to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the remaining impurities were purified by medium pressure liquid chromatography to give the product 26-5 (240 mg, 807.13 μmol, 31.68% yield), LCMS (ESI + ) m / z: 298.4 [M+H] + . Step 3: Synthesis of compound 26-6: In a dry one-neck flask, substrate 26-5 (240 mg, 807.13 μmol) and methanol (10 mL) were added and stirred until homogenous. Pd / C (30 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to give product 26-6 (160 mg, 598.43 μmol, 74.14% yield), LCMS (ESI + ) m / z: 268.4 [M+H] + . Step 4: Synthesis of compound 26: In a dry one-neck flask, the substrate IM-1 (47.5 mg, 132.89 μmol) and tetrahydrofuran (0.5 mL) were added, stirred and dissolved, and then m-CPBA (54 mg, 265.79 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (85.88 mg, 664.47 μmol, 115.74 μL) was added, stirred for 10 min, and then compound 26-6 (21.70 mg, 99.88 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 26 (1.5 mg, 2.35 μmol, 1.77% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.37(s,1H),8.90(s,1H),8.11(t,J=8.2Hz,1H),7.80(dd,J=8.3,6.2Hz,2H),7.63(d,J =7.7Hz,1H),7.58(d,J=8.4Hz,2H),7.54(d,J=8.5Hz,2H),7.01(d,J=8.8Hz,2H),5.68(dd t,J=16.5,10.3,5.9Hz,1H),5.35(s,1H),5.01(d,J=10.2Hz,1H),4.88-4.79(m,1H),4.70 (d,J=6.0Hz,2H),3.18(t,J=5.0Hz,4H),2.47(t,J=5.0Hz,4H),2.23(s,3H),1.47(s,6H). LCMS(ESI)m / z:577.3 [M+H] + ,HPLC Method B:R T=9.20min, purity:97.8%.

[0065] <Example 27: Synthesis of Compound 27> TIFF2025503478000114.tif67170 Step 1: Synthesis of compound 27-2: In a dry one-neck flask, substrate 27-1 (400 mg, 2.02 mmol) and DMSO (5 mL) were added, stirred and dissolved, then potassium carbonate (836.50 mg, 6.05 mmol) and p-fluoronitrobenzene (313.14 mg, 2.22 mmol) were added, heated to 65 °C and reacted for 10 hours, and monitored by LC-MS. After the reaction was completed, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography to obtain the following: product 27-2 (633 mg, 1.98 mmol, 98.24% yield), LCMS (ESI + ) m / z: 320.4 [M+H] + . Step 2: Synthesis of compound 27-3: In a dry one-neck flask, substrate 27-2 (633 mg, 1.98 mmol) and methanol (5 mL) were added and stirred until homogenous. Pd / C (60 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After the reaction was completed, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to obtain the following: product 27-3 (459 mg, crude), LCMS (ESI + ) m / z: 290.4 [M+H] + . Step 3: Synthesis of compound 27-4: In a dry one-neck flask, the substrate 27-3 (150 mg, 518.36 μmol) and THF (5 mL) were added, stirred and dissolved, and then LiAlH4 (19.67 mg, 518.36 μmol) was added. The reaction was heated to 65 °C and reacted for 4 hours, and monitored by LC-MS. After the reaction was completed, 10% aqueous sodium hydroxide solution was added in an ice bath to quench the reaction, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to obtain the following product 27-4 (36.59 mg, 180.00 μmol, 34.73% yield), LCMS (ESI + ) m / z: 204.3 [M+H] + . Step 4: Synthesis of compound 27: In a dry one-neck flask, the substrate IM-1 (53.61 mg, 0.15 mmol) and tetrahydrofuran (0.5 mL) were added, stirred and dissolved, and then m-CPBA (38.83 mg, 225.00 μmol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction was completed, DIPEA (96.93 mg, 750.00 μmol, 130.63 μL) was added, stirred for 10 min, and then compound 27-4 (36.59 mg, 180.00 μmol) was added, and monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 27 (18.9 mg, 33.81 μmol, 22.54% yield). 1 H NMR (600MHz, DMSO-d6) δ 10.10(s,1H),8.80(s,1H),8.03(s,1H),7.77(s,1H),7.60(d,J=7.7Hz,3H), 6.72(d,J=8.5Hz,2H),5.70-5.61(m,1H),5.32(s,1H),4.99(dd,J=10.3,1.6H z,1H),4.83(dd,J=17.1,1.7Hz,1H),4.68(d,J=6.1Hz,2H),3.64(s,2H),3.46 (d,J=10.9Hz,2H),2.51(s,3H),2.05-1.98(m,2H),1.57(s,1H),1.46(s,6H). LCMS(E+)m / z:513.2 [M+H] + ,HPLC Method BR T=11.32min, Purity: 92.6%.

[0066] <Example 28: Synthesis of compound 28> TIFF2025503478000115.tif69170 Step 1: Synthesis of compound 28-2: In a dry one-neck flask, substrate 28-1 (332 mg, 1.56 mmol) and DMSO (5 mL) were added, stirred and dissolved, then potassium carbonate (648.42 mg, 4.69 mmol) and p-fluoronitrobenzene (242.73 mg, 1.72 mmol) were added, and the reaction was heated to 80 °C for 12 hours and monitored by LC-MS. After the reaction was completed, water and ethyl acetate were added, extracted three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography to obtain the following: product 28-2 (512 mg, 1.54 mmol, 98.20% yield), LCMS (ESI + ) m / z: 334.4 [M+H] + . Step 2: Synthesis of compound 28-3: In a dry one-neck flask, substrate 28-2 (640 mg, 1.92 mmol) and methanol (5 mL) were added and stirred until homogenous. Pd / C (60 mg) was added and the mixture was purged with hydrogen gas five times. The reaction was stirred at room temperature and monitored by LC-MS. After completion of the reaction, Pd / C was removed with diatomaceous earth, washed with methanol, and the organic phase was concentrated under reduced pressure to obtain the following: product 28-3 (570 mg, crude), LCMS (ESI + ) m / z: 304.2 [M+H] + . Step 3: Synthesis of compound 28-4: In a dry one-neck flask, the substrate 28-3 (200 mg, 659.20 μmol) and THF (5 mL) were added, stirred and dissolved, and then LiAlH4 (125.08 mg, 3.30 mmol) was added. The reaction was heated to 65 °C and reacted for 4 hours, and monitored by LC-MS. After the reaction was completed, 10% aqueous sodium hydroxide solution was added in an ice bath to quench the reaction, and the filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography to obtain the following product 28-4 (89 mg, 409.55 μmol, 62.13% yield), LCMS (ESI + ) m / z: 218.2 [M+H] + . Step 4: Synthesis of compound 28: In a dry one-neck flask, the substrate IM-1 (53.61 mg, 0.15 mmol) and tetrahydrofuran (1 mL) were added, stirred and dissolved, and then m-CPBA (38.83 mg, 225.00 μmol) was added, and the reaction was carried out at room temperature for 1 h and monitored by LC-MS. After the reaction was completed, DIPEA (96.93 mg, 750.00 μmol, 130.63 μL) was added, and after stirring for 10 min, compound 28-4 (32.60 mg, 150.00 μmol) was added, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (base method) to obtain the following: compound 28 (26.8 mg, 48.90 μmol, 32.60% yield). 1 H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.81(s,1H),8.04(s,1H),7.75(s,1H),7.65-7.43(m,3H),6.79(d,J=8.6H z,2H),5.66(ddt,J=16.4,10.2,6.0Hz,1H),5.32(s,1H),4.99(dd,J=10.3,1.4Hz,1H),4. 82(dd,J=17.1,1.5Hz,1H),4.68(d,J=5.9Hz,2H),3.35(d,J=10.5Hz,2H),3.24(s,2H),2. 81(d,J=10.3Hz,2H),2.25(s,3H),2.00-1.94(m,2H),1.66(d,J=7.6Hz,2H),1.46(s,6H). LCMS(E+)m / z:527.4 [M+H] +,HPLC Method BR T =10.46min,purity:96.1%.

[0067] <Example 29: Synthesis of Compound 29> TIFF2025503478000116.tif51170 Step 1: Synthesis of compound 29-2 In a dry one-neck flask, substrate 29-1 (233 mg, 891.63 μmol) and methanol (10 mL) were added, stirred and dissolved, then palladium carbon (10 mg) was added, hydrogen gas was replaced five times, and the reaction was carried out at room temperature for 2 hours and monitored by LC-MS. After the reaction was completed, it was filtered through diatomaceous earth, washed with methanol, and the organic phase was concentrated by vacuum distillation to obtain the following: compound 29-2 (200 mg, 866 μmol), LCMS (ESI) m / z: 232.2 [M+H] + . Step 2: Synthesis of compound 29 In a dry one-neck flask, the substrate IM-1 (38.63 mg, 108.07 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (30 mg, 162.10 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (20.95 mg, 162.10 μmol) and 29-2 (25 mg, 0.18 mmol) were added to the reaction solution and reacted at room temperature overnight. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 29 (18 mg, 33.29 μmol). LCMS (ESI) m / z: 541.4 [M+H] + , HPLC method BR T =5.14min, purity >90.0%. 1H NMR (600MHz, methanol-d4) δ 8.76(s,1H), 7.95-7.93(m,1H), 7.76-7.74(m,1H), 7.62(d,J=7.8Hz,1H), 7.44(s,2H), 6.70-6.62(m,2H), 5.72-5.68(m,1H), 5.03(d,J=10.2Hz,1H), 4.95-4.88(m,2H), 4.80(d, J=6.0Hz,2H),4.00(d,J=8.6Hz,1H),3.94-3.89(m,1H),3.53-3.45(m,4H),3.35(s,3H), 3.22-3.18(m,1H),2.41-2.33(m,2H),2.16-2.12(m,2H),1.98-1.95(m,1H),1.57(s,6H).

[0068] <Example 30: Synthesis of Compound 30> TIFF2025503478000117.tif57170Step 1: Synthesis of compound 30-2 In a dry one-neck flask, substrate 30-1 (200 mg, 912.24 μmol) was added and dissolved in tetrahydrofuran (3 mL), and triethylamine (461 mg, 4.56 mmol) and trifluoroethyl trifluoromethanesulfonate (317 mg, 1.37 mmol) were added. The temperature was raised to 80° C. and stirred overnight. The reaction was monitored by LC-MS. After completion of the reaction, it was concentrated by distillation under reduced pressure to give compound 30-2 (235 mg, 780 μmol), LCMS (ESI) m / z: 302.1 [M+H]. + . Step 2: Synthesis of compound 30-3 In a dry one-neck flask, substrate 30-2 (235 mg, 780 μmol) and methanol (3 mL) were added, stirred and dissolved, then palladium carbon (25 mg) was added, hydrogen gas was replaced five times, and the reaction was carried out at room temperature for 2 hours and monitored by LC-MS. After the reaction was completed, it was filtered through diatomaceous earth, washed with methanol, and the organic phase was concentrated by vacuum distillation to obtain the following: compound 30-3 (183 mg, 675 μmol), LCMS (ESI) m / z: 272.2 [M+H] + . Step 3: Synthesis of compound 30 In a dry one-neck flask, the substrate IM-1 (27 mg, 75.54 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (23 mg, 113.31 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (48.81 mg, 377.1 μmol) and 30-3 (30.7 mg, 113.31 μmol) were added to the reaction solution and reacted at room temperature overnight. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 30 (10.7 mg, 18.43 μmol). LCMS (ESI) m / z: 581.3 [M+H] + , HPLC method BRt=8.07min, purity >89.7%. 1 H NMR(600MHz,DMSO-d6)δ 10.11(s,1H),8.80(s,1H),7.99-7.96(m,1H),7.75(s,1H),7.62(d,J=7.8Hz,1H),7.4 7(s,2H),6.62(d,J=8.4Hz,2H),6.19(d,J=23.4Hz,1H),5.69-5.63(m,1H),4.99(d,J=1 0.2Hz,1H),4.83(d,J=17.4Hz,1H),4.67(s,2H),3.89(s,2H),3.51(s,2H),3.29(s,3H) ,2.97(s,3H),2.22(s,2H),2.00(d,J=7.8Hz,2H),1.76(d,J=14.4Hz,1H),1.46(s,6H). D2O: 1 H NMR (600MHz, DMSO-d6) δ 8.81(s,1H),8.01-7.98(m,1H),7.74(s,1H),7.62(d,J=7.8Hz,1H),7.49(s,2 H),6.64(d,J=8.4Hz,2H),5.69-5.63(m,1H),5.02(d,J=10.2Hz,1H),4.83(d,J =17.4Hz,1H),4.68(s,2H),3.90-3.88(m,2H),3.43-3.42(m,4H),3.14-3.12( m, 1H), 2.97 (s, 3H), 2.23-2.20 (m, 2H), 2.03 (s, 2H), 1.82 (s, 1H), 1.47 (s, 6H).

[0069] <Example 31: Synthesis of Compound 31> TIFF2025503478000118.tif61170Step 1: Synthesis of compound 31-2 In a dry one-neck flask, substrate 31-1 (2.0 g, 7.80 mmol) and methanol (10 mL) were added, stirred and dissolved, then palladium carbon (200 mg) was added, hydrogen gas was replaced five times, and the reaction was carried out at room temperature for 2 hours and monitored by LC-MS. After the reaction was completed, it was filtered through diatomaceous earth, washed with methanol, and the organic phase was concentrated by vacuum distillation to obtain the following: compound 31-2 (1.6 g, 7.07 mmol), LCMS (ESI) m / z: 232.2 [M+H] + . Step 2: Synthesis of compound 31 In a dry one-neck flask, the substrate IM-1 (100 mg, 279.78 μmol) was added and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (120 mg, 559.55 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (180.79 mg, 1.40 mmol) and 31-2 (126.61 mg, 559.55 μmol) were added to the reaction solution and reacted at room temperature overnight. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 31 (40 mg, 74.68 μmol). LCMS (ESI) m / z: 536.2 [M+H] + ,HPLC Method B:R T =8.58min, Purity:>96.1%. 1H NMR(600MHz,DMSO-d6)δ 10.33(s,1H),8.89(s,1H),8.04-8.02(m,1H),7.80-7.71(m,3H),7.61(d,J=7.8H z,1H),7.23(d,J=8.4Hz,2H),6.81(d,J=7.4Hz,1H),6.73-6.71(m,1H),6.70-6.6 7(m,2H),5.68-5.64(m,1H),5.32(s,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.4 Hz,1H),4.69(d,J=6.0Hz,2H),4.27-4.26(m,2H),3.68-3.66(m,2H),1.46(s,7H)

[0070] <Example 32: Synthesis of Compound 32> TIFF2025503478000119.tif47170 Step 1: Synthesis of compound 32-1 In a dry one-neck flask, 4-1 (800 mg, 6.39 mmol) was dissolved in ethanol (10 mL), and water, potassium oxide (717 mg, 12.78 mmol), and p-nitrobenzaldehyde (1.16 g, 7.67 mmol) were added in sequence. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was monitored by LC-MS and concentrated under reduced pressure. The residue was purified by MPLC to give compound 32-1 (863 mg, 3.34 mmol). LCMS (ESI) m / z: 259.1 [M+H] + . Step 2: Synthesis of compound 32-2 In a one-neck flask, trimethylsulfonium iodide (2.94 g, 13.37 mmol) and sodium hydroxide (1.07 g, 26.73 mmol) were added, dissolved in tetrahydrofuran (20 mL), purged with nitrogen, and reacted at room temperature for 1 hour. 32-1 (863 mg, 3.34 mmol) was added, purged with nitrogen again, stirred at 65 ° C for 1 hour, and the reaction was monitored by LCMS. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and ethyl acetate and water were added and extracted three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 32-2 (493 mg, 1.81 mmol). LCMS (ESI) m / z: 273.1 [M + H] + . Step 3: Synthesis of compound 32-3 In a dry one-neck flask, the substrate 32-2 (493 mg, 1.81 mmol) and methanol (5 mL) were added, stirred and dissolved, then palladium carbon (50 mg) was added, hydrogen gas was replaced five times, and the reaction was carried out at room temperature for 2 hours and monitored by LC-MS. After the reaction was completed, it was filtered through diatomaceous earth, washed with methanol, and the organic phase was concentrated by vacuum distillation to obtain the following: compound 32-3 (395 mg, 1.63 mmol), LCMS (ESI) m / z: 243.2 [M+H] + . Step 4: Synthesis of compound 32 In a dry one-neck flask, the substrate IM-1 (36 mg, 100.72 μmol) was added and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (26 mg, 151 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (65 mg, 504 μmol) and 32-3 (48.8 mg, 201 μmol) were added to the reaction solution and reacted at room temperature overnight. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 32 (7.2 mg, 13.05 μmol). LCMS (ESI) m / z: 552.3 [M+H] + ,HPLC Method A:R T =9.90min, Purity:>99.1%. 1H NMR(600MHz,DMSO-d6)δ 10.26(s,1H),8.88(s,1H),8.04-8.02(m 1H),7.75(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,3H),7.26(d,J=8.4Hz,2H),5.67-5.65(m,1H),5.34(s ,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.4Hz,1H),4.69(d,J=6.0Hz,2H),2.96-2.93(m,2H),2.7 7-2.70(m,1H),2.49(d,J=12.6Hz,1H),2.45-2.43(m,1H),2.21-2.20(m,1H),2.01-1.97(m,1H),1. 92-1.89(m,2H),1.87-1.79(m,J=2.6Hz,1H),1.67-1.62(m,1H),1.59(d,J=9.6Hz,1H),1.46(s,6H).

[0071] <Example 33: Synthesis of Compound 33> TIFF2025503478000120.tif52170Step 1: Synthesis of compound 33-2 In a dry one-neck flask, 23-5 (100 mg, 404.38 μmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (409.19 mg, 4.04 mmol) and 33-1 (140.79 mg, 606.57 μmol) were added in sequence. The reaction mixture was stirred at 80° C. for 3 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by MPLC to give compound 33-2 (70 mg, 212.56 μmol). LCMS (ESI) m / z: 330.1 [M+H] + . Step 2: Synthesis of compound 33-3 In a 50 mL round-bottom flask, 33-2 (80 mg, 0.24 mmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (10 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 33-3 (20 mg, 0.17 mmol). LCMS (ESI) m / z: 300.2 [M+H] + . Step 3: Synthesis of compound 33 In a dry one-neck flask, the substrate IM-6 (48.55 mg, 130.00 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (84.01 mg, 650.00 μmol) and 33-3 (44 mg, 146.99 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 33 (20 mg, 31.77 μmol). LCMS (ESI) m / z: 609.2 [M+H] + ,HPLC Method A:R T =5.8min, purity: 96.7%. 1 H NMR(600MHz,DMSO-d6)δ 10.08(s,1H),8.80(s,1H),8.01-8.00(m,1H),7.77(s,1H),7.60(d,J=7.8Hz,1H),7.54-7.40(m,2H),6.75(d,J=8.4H) z,2H),5.67-5.63(m,1H),5.37(s,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=16.8Hz,1H),4.69(s,2H),3.47(s,2H),3.08 (s,4H),2.95(s,2H),2.70(s,2H),2.07(s,2H),1.66-1.59(m,2H),1.47(s,6H). D2O: 1 H NMR (600MHz, DMSO-d6) δ 8.81(s,1H),8.02-8.01(m,1H),7.75(s,1H),7.61(d,J=7.2Hz,1H),7.54(s,2H) ,6.75(d,J=7.8Hz,2H),5.68-5.64(m,1H),5.02(d,J=10.2Hz,1H),4.84(d,J=16 .8Hz,1H),4.70(s,2H),3.52(d,J=10.8Hz,2H),3.09-3.04(m,4H),2.94(d,J=10 .2Hz,2H),2.69(d,J=10.2Hz,2H),2.08(s,2H),1.67-1.58(m,2H),1.48(s,6H).

[0072] <Example 34: Synthesis of compound 34> TIFF2025503478000121.tif55170 Step 1: Synthesis of compound 34-1 In a dry one-neck flask, the substrate 23-5 (100 mg, 404.38 μmol) was added and dissolved in N,N-dimethylformamide (3 mL), 2-bromoethyl methyl ether (84 mg, 606 μmol), potassium carbonate (111.77 mg, 808.76 μmol) and potassium iodide (13.43 mg, 80.88 μmol) were added, and the reaction was carried out at 85 ° C for 3 hours. LC-MS was used for monitoring. Upon completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 34-1 (65 mg, 212.86 μmol). LCMS (ESI) m / z: 306.2 [M+H] + . Step 2: Synthesis of compound 34-2 In a 50 mL round-bottom flask, 34-1 (80 mg, 261.98 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (10 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 34-2 (29 mg, 0.10 mmol). LCMS (ESI) m / z: 276.2 [M+H] + . Step 3: Synthesis of compound 34 In a dry one-neck flask, the substrate IM-6 (37 mg, 99.08 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (64.03 mg, 495.41 μmol) and 34-2 (28.65 mg, 104.04 μmol) were added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 34 (10 mg, 17.10 μmol). LCMS (ESI) m / z: 585.3 [M+H] +, HPLC method A: R T = 5.4 min, purity: 96.4%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.61 - 7.56 (m, 3H), 6.75 (s, 2H), 5.69 - 5.63 (m, 1H), 5.32 (s, 1H), 4.99 (d, J = 10.2 Hz, 1H), 4.83 (d, J = 17.4, 1H), 4.68 (d, J = 4.2 Hz, 2H), 3.54 (d, J = 10.2 Hz, 2H), 3.40 (s, 4H), 3.18 (s, 3H), 3.06 - 2.98 (m, 4H), 2.44 - 2.29 (m, 2H), 2.13 (s, 2H), 1.68 - 1.57 (m, 2H), 1.46 (s, 6H). D2O: 1 1H NMR (600 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.03 (s, 1H), 7.76 - 7.75 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H) 7.56 - 7.50 (m, 2H), 6.77 (s, 2H), 5.69 - 5.63 (m, 1H), 5.01 (d, J = 10.2 Hz, 1H), 4.83 (d, J = 16.8 Hz,, 1H), 4.68 (d, J = 4.8 Hz, 2H), 3.63 (s, 2H), 3.55 (d, J = 10.8 Hz, 2H), 3.41 (s, 2H), 3.18 (s, 3H), 3.05 - 2.96 (m, 4H), 2.45 - 2.36 (m, 2H), 2.14 (s, 2H), 1.66 - 1.63 (m, 2H), 1.47 (s, 6H).

[0073] <Example 35: Synthesis of Compound 35> TIFF2025503478000122.tif59170 Step 1: Synthesis of Compound 35-2 In a 100 mL dry round bottom flask, 35-1 (2.59 g, 11 mmol) was added under nitrogen protection, and tetrahydrofuran (25 mL) was added to dissolve. The temperature was lowered to -78 °C, and n-LiBu (5.5 mL, 2 M in THF, 11 mmol) was slowly added dropwise to the reaction system. After stirring at -78 °C for 30 minutes, N-methyl-4-piperidinone (1.24 g, 11.00 mmol) was added. After slowly warming to room temperature, the mixture was stirred for 1 hour. The reaction was quenched with saturated NH4Cl solution and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: compound 35-2 (2.63 g, 9.73 mmol). LCMS (ESI) m / z: 270.1 [M + H] + . Step 2: Synthesis of compound 35-3 In a dry microwave tube, substrate 35-2 (675.4 mg, 2.5 mmol), aqueous ammonia (1.75 g, 50.00 mmol), cuprous oxide (17.9 mg, 0.125 mmol), sodium iodide (242.66 mg, 1.62 mmol), potassium carbonate (69.10 mg, 0.5 mmol) and N,N'-dimethylethylenediamine (22 mg, 0.25 mmol) were added under nitrogen protection, and then ethylene glycol (5 mL) was added. The reaction was heated at 110 °C for 12 hours under nitrogen atmosphere. After completion of the reaction, monitored by LC-MS, the reaction was cooled to room temperature, filtered, extracted with ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: compound 35-3 (346 mg, 1.68 mmol). LCMS(ESI)m / z:207.2 [M+H] + . Step 3: Synthesis of compound 35 In a dry one-neck flask, the substrate IM-1 (71.5 mg, 0.2 mmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (51.8 mg, 0.3 mmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (129.2 mg, 1.00 mmol) and 35-3 (61.9 mg, 0.3 mmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 35 (16 mg, 31.03 μmol). 1 H NMR(600MHz,DMSO-d6)δ 10.27(s,1H),8.88(s,1H),8.06-8.04(m,1H),7.76(d,J=8.4Hz,1H),7.65(d,J=26.4 Hz,3H),7.43(d,J=8.4Hz,2H),5.67-5.64(m,1H),5.34(s,1H),5.00(d,J=10.2Hz,1H ),4.83(d,J=17.4Hz,1H),4.73(s,1H),4.68(d,J=6.0Hz,2H),2.58(d,J=10.8Hz,2H) ,2.40-2.38(m,2H),2.23(s,3H),2.01-1.91(m,2H),1.61-1.55(m,2H),1.46(s,6H). LCMS(ESI)m / z:516.3 [M+H] + , HPLC T =4.68min,purity >92.7%.

[0074] <Example 36: Synthesis of Compound 36> TIFF2025503478000123.tif87170 Step 1: Synthesis of compound 36-2 In a dry one-neck flask, 36-1 (5 g, 44.22 mmol) was added and dissolved in dichloromethane (50 mL). Triethylamine (8.95 g, 88.44 mmol, 12.33 mL), 4-dimethylaminopyridine (540.22 mg, 4.42 mmol) and di-tert-butyl dicarbonate (10.62 g, 48.64 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was diluted with water and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 36-2 (4.62 g, 21.67 mmol). LCMS (ESI) m / z: 214.1 [M+H] + . Step 2: Synthesis of compound 36-3 In a 50 mL round-bottom flask, 36-2 (4.62 g, 21.67 mmol) was added and dissolved in ethanol (3 mL). A catalytic amount of palladium on carbon (400 mg) was added and stirred at room temperature under hydrogen atmosphere for 6 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with ethanol, and the filtrate was concentrated under reduced pressure to give compound 36-3 (3.85 g, 21.01 mmol). LCMS (ESI) m / z: 184.1 [M+H] + . Step 3: Synthesis of compound 36-4 In a dry one-neck flask, the substrate 36-3 (3.85 g, 21.01 mmol) was added and dissolved in methanol (40 mL), and formaldehyde (1.26 g, 42.03 mmol) and acetic acid (2 mL) were added and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (3.30 g, 52.54 mmol) was added, and the temperature was raised to 50 ° C. and reacted for 12 hours. After the reaction was completed, it was diluted with water, adjusted to basicity by adding saturated sodium bicarbonate, and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: compound 36-4 (4.01 g, 18.98 mmol). LCMS (ESI) m / z: 212.1 [M + H] + . Step 4: Synthesis of compound 36-5 In a dry one-neck flask, 36-4 (4.01 g, 18.98 mmol) was added and dissolved in dichloromethane (40 mL). Trifluoroacetic acid (21.64 g, 189.81 mmol, 14.53 mL) was added and the reaction was carried out at room temperature for 30 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain compound 36-5 (1.86 g, 16.73 mmol). LCMS (ESI) m / z: 112.1 [M+H] + . Step 5: Synthesis of compound 36-6 In a dry one-neck flask, 36-5 (1.86 g, 16.73 mmol) was dissolved in dimethyl sulfoxide (15 mL), and p-fluoronitrobenzene (2.36 g, 16.73 mmol) and potassium carbonate (5.78 g, 41.84 mmol) were added in sequence. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography to give compound 36-6 (3.56 g, 15.33 mmol). LCMS (ESI) m / z: 233.1 [M+H] + . Step 6: Synthesis of compound 36-7 In a dry one-neck flask, 36-6 (3.56 g, 15.33 mmol) was added and dissolved in ethanol (35 mL). A catalytic amount of palladium on carbon (350 mg) was added and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with ethanol, and the filtrate was concentrated under reduced pressure to give compound 36-7 (2.95 g, 14.59 mmol). LCMS (ESI) m / z: 203.1 [M+H] + . Step 7: Synthesis of Compound 36 In a dry one-neck flask, the substrate IM-1 (45.51 mg, 225.00 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (38.83 mg, 225.00 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (96.93 mg, 750.00 μmol) and 36-7 (53.61 mg, 0.15 mmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 36 (9 mg, 17.59 μmol). LCMS (ESI) m / z: 512.2 [M+H] + , HPLC method BR T =7.26min,purity > 98.0%. 1 H NMR(600MHz,DMSO-d6)δ 10.39(s,1H),8.91(s,1H),8.09(s,1H),7.87(s,1H),7.82(d,J=8.4Hz, 2H),7.78(d,J=8.4Hz,1H),7.72(d,J=9.0Hz,2H),7.64(d,J=7.8Hz,1H) ,7.45(s,1H),5.71-5.66(m,1H),5.34(s,1H),5.00(d,J=10.2Hz,1H),4 .84(d,J=17.4Hz,1H),4.70(d,J=6.0Hz,2H),2.70(s,6H),1.47(s,6H).

[0075] <Example 37: Synthesis of Compound 37> TIFF2025503478000124.tif56170 Step 1: Synthesis of compound 37-1 In a dry one-neck flask, the substrate 23-5 (150 mg, 606.57 μmol) was added and dissolved in N,N-dimethylformamide (3 mL), 1,2-fluorobromoethane (84 mg, 661.65 μmol), potassium carbonate (165 mg, 1.19 mmol) and potassium iodide (20 mg, 120.5 μmol) were added, and the reaction was carried out at 90° C. for 3 hours. The reaction was monitored by LC-MS. Upon completion of the reaction, the reaction solution was cooled to room temperature, water was added, filtered, and washed with methanol. The organic phase was concentrated under reduced pressure to give the following: compound 37-1 (80 mg, 272.7 μmol). LCMS (ESI) m / z: 394.2 [M+H] + . Step 2: Synthesis of compound 37-2 In a 50 mL round-bottom flask, 37-1 (80 mg, 272.7 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium carbon (10 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 37-2 (50 mg, 0.19 mmol). LCMS (ESI) m / z: 264.2 [M+H] + . Step 3: Synthesis of compound 37 In a dry one-neck flask, the substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 37-2 (30 mg, 113.92 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 37 (25 mg, 42.65 μmol). LCMS (ESI) m / z: 585.3 [M+H] + ,HPLC Method A:R T =5.4min, Purity: 96.4%. 1H NMR(600MHz,Chloroform-d)δ 8.74(s,1H),7.82(s,1H),7.71(d,J=7.8Hz,1H),7.36(s,2H),7.26(d,J=7.2Hz,1H) ,6.76(s,2H),5.67-5.60(m,1H),4.97(d,J=10.2Hz,1H),4.87(d,J=17.4Hz,1H),4. 67(d,J=6.0Hz,2H),4.55-4.74(m,2H),3.94(brs,1H),3.57-3.55(m,2H),3.10-2.9 3(m,4H),2.70-2.51(m,4H),2.12(s,2H),1.67(s,2H),1.51(s,6H),1.25(brs,1H).

[0076] <Example 38: Synthesis of compound 38> TIFF2025503478000125.tif91170 Step 1: Synthesis of compound 38-1 In a dry one-neck flask, IM-4 (500 mg, 1.57 mmol) was added and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 38-1 (330 mg, 1.51 mmol). LCMS (ESI) m / z: 220.1 [M+H] + . Step 2: Synthesis of compound 38-2 In a dry one-neck flask, substrate 38-1 (100 mg, 456.12 μmol) was added and dissolved in N,N-dimethylformamide (2 mL), 2-bromoethanol (57.00 mg, 456.12 μmol), potassium carbonate (94.55 mg, 684.18 μmol) and potassium iodide (15.14 mg, 91.22 μmol) were added, and the reaction was carried out at 90° C. for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, filtered, and washed with methanol. The organic phase was concentrated under reduced pressure to give compound 38-2 (93 mg, 353 μmol). LCMS (ESI) m / z: 264.1 [M+H] + . Step 3: Synthesis of compound 38-3 In a dry one-neck flask under nitrogen protection, substrate 38-2 (93 mg, 353.22 μmol) was added and dissolved in tetrahydrofuran (2.5 mL), and triethylamine (142.97 mg, 1.41 mmol) was added. The system temperature was lowered to 0° C., and acetyl chloride (41.59 mg, 529.83 μmol) was added. The temperature was slowly raised to room temperature and stirred for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure to give compound 38-3 (96 mg, 314.8 μmol). LCMS (ESI) m / z: 292.1 [M+H] + . Step 4: Synthesis of compound 38-4 In a 50 mL round-bottom flask, 38-3 (277 mg, 907.22 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (30 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 38-4 (177 mg, 642 μmol). LCMS (ESI) m / z: 262.2 [M+H] + . Step 5: Synthesis of compound 38-5 In a dry one-neck flask, the substrate IM-1 (40 mg, 111.91 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (38.62 mg, 223.82 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (72.32 mg, 559.55 μmol) and 38-4 (30.81 mg, 111.91 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure to obtain the following: crude product 38-5 (300 mg, crude). LCMS (ESI) m / z: 571.3 [M+H] + . Step 6: Synthesis of compound 38 In a dry one-neck flask, substrate 38-5 (300 mg, crude) was added and dissolved in methanol (3 mL). Water, sodium oxide (41.05 mg, 1.03 mmol) and water (0.2 mL) were added and reacted at room temperature for 30 minutes. After completion of the reaction, the mixture was monitored by LC-MS, concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 38 (10.36 mg, 19.09 μmol). LCMS (ESI) m / z: 543.2 [M+H] + .HPLC Method A:R T =4.82min, Purity: 100.0%. 1 H NMR(600MHz,DMSO-d6)δ 10.04(s,1H),8.79(s,1H),8.02-7.99(m,1H),7.74(s,1H),7.59(d,J=7.2Hz,1H),7.49(s,2H) ,6.55(d,J=7.8Hz,2H),5.67-5.63(m,1H),5.32(s,1H),4.99(d,J=10.2Hz,1H),4.82(d,J=17. 4Hz,1H),4.69-4.67(m,2H),4.37-4.35(m,1H),4.26(s,1H),3.54(s,1H),3.38-3.36(m,3H),3 .14(d,J=9.0Hz,1H),2.87(d,J=9.0Hz,1H),2.48-2.46(m,2H),1.83-1.77(m,2H),1.46(s,6H).

[0077] <Example 39: Synthesis of Compound 39> TIFF2025503478000126.tif58170 Step 1: Synthesis of compound 39 In a dry one-neck flask, the substrate IM-3 (30.49 mg, 150.00 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (25.88 mg, 150.00 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (19.39 mg, 150.00 μmol) and compound 27-4 (30.49 mg, 150.00 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: compound 39 (26 mg, 38.83 μmol). LCMS (ESI) m / z: 546.2 [M+H] + , HPLC method BR T =5.93min,purity > 81.5%. 1 H NMR (600MHz, DMSO-d6) δ 10.07(s,1H),8.78(s,1H),7.78(s,1H),7.61(s,2H),7.32(d,J=7.8Hz,1H),6.7 1(d,J=7.8Hz,2H),6.59(d,J=8.4Hz,1H),5.68-5.60(m,1H),5.00(d,J=10.2Hz, 1H),4.90(d,J=17.4Hz,1H),4.75(s,2H),3.60(s,2H),3.44(d,J=11.4Hz,2H),3 .38(s,6H),3.35(d,J=8.4Hz,2H),2.44(s,1H),2.00(s,3H),1.55-1.53(m,1H).

[0078] <Example 40: Synthesis of compound 40> TIFF2025503478000127.tif49170Step 1: Synthesis of compound 40-2 In a dry one-neck flask, 40-1 (0.4 g, 2 mmol) was dissolved in dimethyl sulfoxide (15 mL), and p-fluoronitrobenzene (0.28 g, 2 mmol) and potassium carbonate (1.11 g, 4 mmol) were added in sequence. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following compound 40-2 (0.63 g, 2.56 mmol). LCMS (ESI) m / z: 248.1 [M+H] + . Step 2: Synthesis of compound 40-3 In a dry one-neck flask under nitrogen protection, substrate 40-2 (71.4 mg, 300 μmol) was added and dissolved in tetrahydrofuran (2.5 mL), and triethylamine (121.4 mg, 1.2 mmol) was added. The system temperature was lowered to 0°C, and acetic anhydride (61.2 mg, 600 μmol) was added. The temperature was slowly raised to room temperature and stirred for 12 hours. The reaction was monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by MPLC to give compound 40-3 (25.3 mg, 87.4 μmol). LCMS (ESI) m / z: 290.2 [M+H] + . Step 3: Synthesis of compound 40-4 In a 50 mL round-bottom flask, 40-3 (173 mg, 598 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium on carbon (18 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 40-4 (122 mg, 470 μmol). LCMS (ESI) m / z: 260.2 [M+H] + . Step 4: Synthesis of compound 40 In a dry one-neck flask, the substrate IM-1 (35.7 mg, 100 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (25.85 mg, 150 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (64.54 mg, 500 μmol) and 40-4 (51.81 mg, 0.2 mmol) were added to the reaction solution, and the temperature was raised to 60 ° C. and reacted for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 40 (18 mg, 31.65 μmol). LCMS (ESI) m / z: 569.3 [M + H] + , HPLC method BRt=6.28min, purity > 63.4%. 1 H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.82(s,1H),8.04(s,1H),7.89(s,1H),7.75(s,1H),7.67-7.47(m,3H),6.93(d,J=8.4H z,2H),5.68-5.64(m,1H),5.32(s,1H),4.99(d,J=10.2Hz,1H),4.82(d,J=17.4Hz,1H),4.68(s,2H),4 .37-4.35(m,1H),4.13-4.06(m,1H),3.69(s,2H),3.62(d,J=7.8Hz,1H),2.66-2.55(m,3H),2.39(s,1 H),1.79(d,J=13.2Hz,1H),1.59(d,J=13.2Hz,1H),1.46(s,6H),1.45-1.42(m,1H),1.36-1.24(m,2H).

[0079] <Example 41: Synthesis of Compound 41> TIFF2025503478000128.tif52170 Step 1: Synthesis of compound 41-1 In a dry one-neck flask, the substrate 38-1 (140 mg, 638.57 μmol) was added and dissolved in N,N-dimethylformamide (3 mL), 2-iodopropane (131 mg, 770.63 μmol), and potassium carbonate (124 mg, 897.25 μmol) were added, and the reaction was carried out at 90 ° C for 3 hours. The reaction was monitored by LC-MS. Upon completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 41-1 (80 mg, 306.14 μmol). LCMS (ESI) m / z: 262.2 [M + H] + . Step 2: Synthesis of compound 41-2 In a 50 mL round-bottom flask, 41-1 (80 mg, 306.14 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium carbon (20 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: Compound 41-2 (60 mg, crude). LCMS (ESI) m / z: 232.2 [M+H] + . Step 3: Synthesis of compound 41 In a dry one-neck flask, the substrate IM-6 (45 mg, 120.50 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (77.87 mg, 602.52 μmol) and 41-2 (30 mg, 129.68 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 41 (20 mg, 36.99 μmol). LCMS (ESI) m / z: 541.3 [M+H] + ,HPLC Method A:R T =5.1min, purity: 95.3%. 1H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),8.02-7.99(m,1H),7.78-7.75(m,1H),7.59(d,J=7.8Hz,1H),7.55- 7.41(m,2H),6.57(d,J=7.8Hz,2H),5.69-5.63(m,1H),5.33(s,1H),4.99(d,J=10.2Hz,1H),4. 84(d,J=16.8Hz,1H),4.68(s,2H),4.26(s,1H),3.71(s,1H),3.32-3.30(m,1H),3.16(d,J=9.0 Hz,1H),3.01(d,J=7.8Hz,1H),2.41-2.36(m,2H),1.81(s,2H),1.46(s,6H),0.98-0.93(m,3H). D2O: 1 H NMR(600MHz,DMSO-d6)δ 8.80(s,1H),8.03-7.99(m,1H),7.73(s,1H),7.60(d,J=7.2Hz,1H),7.49-7.37(m,2H),6 .59(d,J=7.2Hz,2H),5.69-5.63(m,1H),5.02(d,J=10.2Hz,1H),4.83(d,J=16.8Hz,1H),4 .68(s,2H),4.26(s,1H),3.78(s,1H),3.32(d,J=7.8Hz,1H),3.19(d,J=9.0Hz,1H),3.03( d,J=9.0Hz,1H),2.42-2.35(m,2H),1.84(d,J=6.6Hz,2H),1.47(s,6H),1.0-0.94(m,6H).

[0080] <Example 42: Synthesis of Compound 42> TIFF2025503478000129.tif50170 Step 1: Synthesis of compound 42-1 In a dry one-neck flask, 27-2 (330 mg, 1.03 mmol) was added and dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 42-1 (280 mg, crude). LCMS (ESI) m / z: 220.1 [M+H] + . Step 2: Synthesis of compound 42-2 In a dry one-neck flask, the substrate 42-1 (300 mg, 1.37 mmol) was added and dissolved in N,N-dimethylformamide (3 mL), 2-iodopropane (348.92 mg, 2.05 mmol), and potassium carbonate (567.35 mg, 4.11 mmol) were added, and the reaction was carried out at 70 ° C for 12 hours. The reaction was monitored by LC-MS. Upon completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 42-2 (280 mg, 1.07 mmol). LCMS (ESI) m / z: 262.2 [M + H] + . Step 3: Synthesis of compound 42-3 In a 50 mL round-bottom flask, 42-2 (0.8 g, 3.06 mmol) was added and dissolved in methanol (10 mL). A catalytic amount of palladium carbon (80 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 42-3 (500 mg, 2.16 mmol). LCMS (ESI) m / z: 232.2 [M+H] + . Step 4: Synthesis of compound 42 In a dry one-neck flask, the substrate IM-1 (42.89 mg, 120.00 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (31.07 mg, 180.00 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (77.54 mg, 600.00 μmol) and 42-3 (33.31 mg, 144.00 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 42 (30 mg, 51.77 μmol). LCMS (ESI) m / z: 541.4 [M+H] + , HPLC method BR T =7.02min, purity >93.3 %.1 H NMR(600MHz,DMSO-d6)δ 10.09(s,1H),8.80(s,1H),8.03(s,1H),7.76(s,1H),7.60-7.47(m,3H),6.69(d,J=8.4H z,2H),5.68-5.64(m,1H),5.31(s,1H),5.00-4.98(m,1H),4.86-4.79(m,1H),4.68(d,J=5 .4Hz,2H),3.71(d,J=6.0Hz,2H),3.42(d,J=11.2Hz,2H),3.24(d,J=10.8Hz,2H),2.50-2 .43(m,1H),2.37-2.35(m,1H),1.50(d,J=8.4Hz,1H),1.46(s,6H),0.88(d,J=6.0Hz,6H).

[0081] <Example 43: Synthesis of Compound 43> TIFF2025503478000130.tif48170Step 1: Synthesis of compound 43-1 In a dry one-neck flask, the substrate 27-1 (0.33 g, 1.66 mmol) was added and dissolved in methanol (4 mL), and formaldehyde (226.77 mg, 6.66 mmol) and acetic acid (0.5 mL) were added and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (1.41 g, 6.66 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, it was diluted with water and extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 43-1 (300 mg, 1.41 mmol). LCMS (ESI) m / z: 213.2 [M+H] + . Step 2: Synthesis of compound 43-2 In a dry one-neck flask, 43-1 (300 mg, 1.41 mmol) was added and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. After the raw material was consumed by monitoring with LC-MS, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 43-2 (0.12 g, 1.07 mmol). Step 3: Synthesis of compound 43-3 In a dry one-neck flask, 43-2 (0.22 g, 1.96 mmol) was dissolved in dimethyl sulfoxide (5 mL), and p-fluoronitrobenzene (304.41 mg, 2.16 mmol) and potassium carbonate (1.36 g, 9.81 mmol) were added in sequence. The reaction mixture was stirred at 100° C. for 3 hours. After completion of the reaction, monitored by LC-MS, it was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 43-3 (260 mg, 1.11 mmol). LCMS (ESI) m / z: 234.1 [M+H] + . Step 4: Synthesis of compound 43-4 In a 50 mL round-bottom flask, 43-3 (0.3 g, 1.29 mmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 43-4 (200 mg, 983.85 μmol). LCMS (ESI) m / z: 204.2 [M+H] + . Step 5: Synthesis of compound 43 In a dry one-neck flask, the substrate IM-1 (42.89 mg, 120.00 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (31.07 mg, 180.00 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (77.54 mg, 600.00 μmol) and compound 43-4 (29.27 mg, 144.00 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: compound 43 (32 mg, 55.12 μmol). LCMS (ESI) m / z: 513.2 [M+H] + ,HPLC Method BR T =6.47min, purity > 88.3%. 1H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.80(s,1H),7.99-7.97(m,1H),7.74(s,1H),7.60-7.58(m,1H),7.48(s,2 H),6.45(d,J=8.4Hz,2H),5.64-5.63(m,1H),5.31(s,1H),4.99(d,J=10.2Hz,1H),4.83(d ,J=17.4Hz,1H),4.68(d,J=5.6Hz,2H),4.23(d,J=5.6Hz,2H),2.97(d,J=10.8Hz,2H),2. 71(d,J=11.4Hz,2H),2.42-2.39(m,1H),2.08(s,3H),1.96(d,J=7.2Hz,1H),1.46(s,6H).

[0082] <Example 44: Synthesis of compound 44> TIFF2025503478000131.tif51170 Step 1: Synthesis of compound 44-1 In a dry one-neck flask, the substrate 38-1 (300 mg, 1.37 mmol) was added and dissolved in N,N-dimethylformamide (2 mL), 1,2-fluorobromoethane (173.72 mg, 1.37 mmol), potassium carbonate (378 mg, 2.74 mmol) and potassium iodide (45.43 mg, 273.67 μmol) were added, and the reaction was carried out at 90 ° C overnight. The reaction was monitored by LC-MS. Upon completion of the reaction, the reaction solution was cooled to room temperature, water was added, filtered, and washed with methanol. The organic phase was concentrated under reduced pressure to give the following: compound 44-1 (320 mg, 1.21 mmol). LCMS (ESI) m / z: 266.1 [M + H] + . Step 2: Synthesis of compound 44-2 In a round-bottom flask, 44-1 (320 mg, 1.21 mmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium carbon (30 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 44-2 (200 mg, 849.98 μmol). LCMS (ESI) m / z: 236.2 [M+H] + . Step 3: Synthesis of compound 44 In a dry one-neck flask, the substrate IM-1 (74 mg, 207.03 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (90 mg, 414.07 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (133.79 mg, 1.04 mmol, 180.30 μL) and 44-2 (97.43 mg, 414.07 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 44 (11.5 mg, 21.12 μmol). LCMS (ESI) m / z: 545.3 [M+H] + ,HPLC Method A:R T =4.95min, Purity:>84.1%. 1 H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.79(s,1H),8.02-8.00(m,1H),7.74(s,1H),7.59(d,J=7.8Hz,1H),7.50(s,2H),6.57(d,J= 8.4Hz,2H),5.68-5.65(m,1H),5.31(s,1H),4.99(d,J=10.2,1H),4.82(d,J=17.4Hz,1H),4.67(s,2H),4.49 -4.42(m,1H),4.38-4.36(m,1H),4.29(s,1H),3.57(s,1H),3.35(d,J=9.0Hz,1H),3.12(d,J=9.0Hz,1H),2. 90(d,J=9.6Hz,1H),2.83-2.64(m,2H),2.53(d,J=9.6Hz,1H),1.84(d,J=9.6Hz,1H),1.79(d,J=9.0Hz,1H).

[0083] <Example 45: Synthesis of Compound 45> TIFF2025503478000132.tif46170Step 1: Synthesis of compound 45-2 In a dry microwave tube, substrate 36-1 (1.13 g, 9.99 mmol), 45-1 (2.20 g, 10.99 mmol), cuprous iodide (1.90 g, 9.99 mmol), potassium carbonate (1.38 g, 9.99 mmol) and N,N'-dimethylethylenediamine (880.93 mg, 9.99 mmol) were added under nitrogen protection, followed by 1,4-dioxane (15 mL). The reaction was heated at 120 °C for 3 hours under nitrogen atmosphere. After completion of the reaction monitored by LCMS, the reaction was cooled to room temperature, filtered, extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to give the following: compound 45-2 (0.8 g, 3.44 mmol). LCMS(ESI)m / z:233.1 [M+H] + . Step 2: Synthesis of compound 45-3 In a 50 mL round-bottom flask, 45-2 (800 mg, 3.44 mmol) was added and dissolved in methanol (10 mL). A catalytic amount of palladium on carbon (40 mg) was added and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 45-3 (500 mg, 2.47 mmol). LCMS (ESI) m / z: 203.1 [M+H] + . Step 3: Synthesis of compound 45 In a dry one-neck flask, the substrate IM-1 (39 mg, 109.11 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (28.25 mg, 163.67 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (70.51 mg, 545.56 μmol, 95.02 μL) and 45-3 (33.10 mg, 163.67 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 45 (32 mg, 62.55 μmol). LCMS (ESI) m / z: 512.2 [M+H] + , HPLC method BRT =7.60min,purity > 100.0%. 1 H NMR(600MHz,DMSO-d6)δ 10.47(s,1H),8.85(s,1H),8.41(s,1H),8.04-8.01(m,1H),7.88(d,J=7.8Hz,1H),7.79-7.68(m,2H),7.52(d,J=9.0Hz,2H),6.88(d,J= 8.4Hz,2H),5.71-5.64(m,1H),5.34(s,1H),5.00(d,J=10.2Hz,1H),4.85-4.77(m,1H),4.65(d,J=6.0Hz,2H),2.97(s,6H),1.46(s,6H).

[0084] <Example 46: Synthesis of Compound 46> TIFF2025503478000133.tif61164 Step 1: Synthesis of compound 46-2 In a dry one-neck flask, sodium methanol (297 mg, 5.52 mmol), nitromethane (306.35 mg, 5.02 mmol) and methanol (8 mL) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Substrate 46-1 (1 g, 5.02 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and acetic acid was added dropwise to adjust the pH value to 7.0. It was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 46-2 (640 mg, 2.46 mmol). Step 2: Synthesis of compound 46-3 In a 50 mL round-bottom flask, 46-2 (100 mg, 384.19 μmol) was added and dissolved in methanol (2 mL). A catalytic amount of palladium carbon (40 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 46-3 (80 mg, 347.4 μmol). LCMS (ESI) m / z: 236.2 [M+H] + . Step 3: Synthesis of compound 46-4 In a dry one-neck flask, the substrate 46-3 (1 g, 4.34 mmol) was added and dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.2 g, 8.68 mmol) and chloroacetyl chloride (540.40 mg, 4.78 mmol) were added, and the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: compound 46-4 (480 mg, 1.56 mmol). LCMS (ESI) m / z: 266.1 [M+H] + . Step 4: Synthesis of compound 46-5 In a dry one-neck flask, substrate 46-4 (60 mg, 195.58 μmol) was added and dissolved in isopropanol (6 mL), potassium tert-butoxide (112 mg, 998.13 μmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the following: crude product 46-5 (50 mg, crude). LCMS (ESI) m / z: 215.1 [M+H] + . Step 5: Synthesis of compound 46-6 In a dry one-neck flask, the substrate 46-5 (26 mg, 96.18 μmol) was added and dissolved in tetrahydrofuran (4.4 mL), and 2M borane tetrahydrofuran solution (0.19 mL, 384.72 μmol) was added and stirred at 70° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and methanol and N,N,N',N'-tetramethylethylenediamine were added and stirred at 78° C. overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the following: crude product 46-6 (25 mg, crude). LCMS (ESI) m / z: 257.2 [M+H] + . Step 6: Synthesis of compound 46-7 In a dry one-neck flask, 46-6 (25 mg, 97.53 μmol) was dissolved in dimethyl sulfoxide (2 mL), and p-fluoronitrobenzene (13.76 mg, 97.53 μmol) and potassium carbonate (19 mg, 137.48 μmol) were added in sequence. The reaction mixture was stirred at 100° C. for 5 hours. After completion of the reaction, monitored by LC-MS, it was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 46-7 (30 mg, 79.48 μmol). LCMS (ESI) m / z: 234.1 [M+H] + . Step 7: Synthesis of compound 46-8 In a dry one-neck flask, 46-7 (18 mg, 47.69 μmol) was added and dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. After the raw material was consumed by monitoring with LC-MS, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 46-8 (13 mg, crude). Step 8: Synthesis of compound 46-9 In a dry one-neck flask, the substrate 46-8 (13 mg, 46.88 μmol) was added and dissolved in methanol (2 mL), and formaldehyde (16 mg, 469.76 μmol) and acetic acid (50 μL) were added and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (10 mg, 159.13 μmol) was added and reacted at 50° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by MPLC to obtain the following: compound 46-9 (10 mg, 34.32 μmol). LCMS (ESI) m / z: 262.2 [M+H] + . Step 9: Synthesis of compound 46-10 In a 50 mL round-bottom flask, 46-9 (50 mg, 171.62 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 46-10 (30 mg, 114.7 μmol). LCMS (ESI) m / z: 236.2 [M+H] + . Step 10: Synthesis of Compound 46 In a dry one-neck flask, the substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (4 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 46-10 (30 mg, 114.78 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 46 (32 mg, 56.07 μmol). LCMS (ESI) m / z: 571.2 [M+H] + ,HPLC Method B:R T =6.53min, purity: 99.5%. 1 H NMR(600MHz,DMSO-d6)δ 10.15(s,1H),8.83(s,1H),8.04(s,1H),7.75(d,J=6.6Hz,1H),7.62-7.59(m,3H),6.91(d,J=8.4Hz,2H),5. 70-5.63(m,1H),5.34(s,1H),5.02-4.99(m,1H),4.83(d,J=16.8Hz,1H),4.68(d,J=5.4Hz,2H),3.81-3.74( m,2H),3.20(d,J=12.0Hz,1H),3.16-3.14(m,1H),2.99-2.96(m,1H),2.89(d,J=12.0Hz,1H),2.66-2.64(m, 1H),2.32(s,1H),2.32-2.21(m,5H),1.74-1.66(m,2H),1.57-1.52(m,1H),1.46(s,6H),1.44-1.38(m,1H). D2O: 1H NMR(600MHz,DMSO-d6)δ 8.83(s,1H),8.05(s,1H),7.74(d,J=7.2Hz,1H),7.63-7.59(m,3H),6.92(d,J=9.0Hz,2H),5. 70-5.63(m,1H),5.02(d,J=10.2Hz,1H),4.83(d,J=17.4Hz,1H),4.69(d,J=5.4Hz,2H),3.82-3 .77(m,2H),3.18-3.13(m,2H),3.00-2.96(m,1H),2.91(d,J=12.0Hz,1H),2.67-2.64(m,1H),2 .51-2.44(m,2H),2.35-2.26(m,4H),1.71-1.67(m,2H),1.57-1.54(m,1H),1.50-1.47(m,7H).

[0085] <Example 47: Synthesis of compound 47> TIFF2025503478000134.tif78170 Step 1: Synthesis of compound 47-1 In a dry one-neck flask, 4-1 (323 mg, 2 mmol) was dissolved in ethanol (10 mL), and water, potassium oxide (337 mg, 6 mmol), and p-bromobenzaldehyde (370 mg, 2 mmol) were added in sequence. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was monitored by LC-MS and concentrated under reduced pressure. The residue was purified by MPLC to give compound 47-1 (456 mg, 1.6 mmol). LCMS (ESI) m / z: 292.1 [M+H] + . Step 2: Synthesis of compound 47-2 In a one-neck flask, trimethylsulfonium iodide (1.6 g, 8 mmol) and sodium hydroxide (0.64 g, 16 mmol) were added, dissolved in tetrahydrofuran (20 mL), purged with nitrogen, and reacted at room temperature for 1 hour. 47-1 (582 mg, 2 mmol) was added, purged with nitrogen again, stirred at 65 ° C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and ethyl acetate and water were added and extracted three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 47-2 (284 mg, 0.93 mmol). LCMS (ESI) m / z: 306.1 [M + H] + . Step 3: Synthesis of compound 47-3 In a dry one-neck flask, the substrate IM-3 (78 mg, 0.2 mol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (52 mg, 0.3 mmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (129 mg, 1 mmol) and aqueous ammonia (0.1 mL, 0.4 mmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 47-3 (58 mg, 0.16 mmol). LCMS (ESI) m / z: 585.2 [M+H] + . Step 4: Synthesis of compound 47 In a dry microwave tube, substrate 47-3 (58 mg, 0.16 mmol), 47-2 (70 mg, 0.23 mmol), cuprous iodide (61 mg, 320.29 μmol), potassium carbonate (44.2 mg, 319.83 μmol) and N,N'-dimethylethylenediamine (56 mg, 635.28 μmol) were added under nitrogen protection, followed by 1,4-dioxane (4 mL). The reaction was heated at 110 °C under nitrogen atmosphere for 6 hours. After completion of the reaction, the reaction was monitored by LCMS, cooled to room temperature, and the solvent was removed by vacuum concentration. The residue was purified by MPLC to give the following: compound 47 (61 mg, 104.33 μmol). LCMS (ESI) m / z: 585.2 [M+H] + ,HPLC Method B:R T =6.54min, purity: 100%. 1 H NMR(600MHz,DMSO-d6)δ 10.23(s,1H),8.86(s,1H),7.80-7.77(m,1H),7.63(d,J=8.4Hz,2H),7.30-7.25(m,3H),6.61(d,J=8 .0Hz,1H),5.65-5.62(m,1H),5.00(d,J=10.2Hz,1H),4.90(d,J=17.4Hz,1H),4.75(d,J=6.0Hz,2H),3 .37(s,6H),2.96-2.92(m,2H),2.74-2.72(m,1H),2.50-2.47(m,1H),2.44-2.43(m,1H),2.22-2.21(m ,1H),1.99-1.98(m,1H),1.93-1.86(m,2H),1.83-1.82(m,1H),1.65-1.63(m,1H),1.60-1.57(m,1H). Step 5: Synthesis of compounds 47a and 47b Compound 47 (20 mg) was resolved by SFC to give: 47a (6 mg), LCMS (ESI) m / z: 585.2 [M+H] + ,HPLC Method B:R T = 6.72 min, purity: 98.7%. and 47b (8.6 mg), LCMS (ESI) m / z: 585.2 [M+H] + ,HPLC Method B:R T =6.75min, purity: 99.6%.

[0086] <Example 48: Synthesis of compound 48> TIFF2025503478000135.tif48170Step 1: Synthesis of compound 48-1 In a dry one-neck flask, substrate 27-2 (100 mg, 456.12 μmol) was added and dissolved in N,N-dimethylformamide (2 mL), 1-bromo-2-fluoroethane (86.86 mg, 684.18 μmol), potassium carbonate (88.25 mg, 638.57 μmol) and potassium iodide (8 mg, 48.19 μmol) were added, and the reaction was carried out at 100° C. for 7.5 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 48-1 (60 mg, 226.17 μmol). LCMS (ESI) m / z: 266.2 [M+H] + . Step 2: Synthesis of compound 48-2 In a 50 mL round-bottom flask, 48-1 (60 mg, 226.17 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium carbon (15 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: Compound 48-2 (45 mg, crude). LCMS (ESI) m / z: 236.2 [M+H] + . Step 3: Synthesis of compound 48 In a dry one-neck flask, the substrate IM-6 (42 mg, 112.47 μmol) and tetrahydrofuran (4 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (72.68 mg, 562.36 μmol) and 48-2 (42 mg, 112.47 μmol) were then added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 48 (45 mg, 74.45 μmol). LCMS (ESI) m / z: 545.2 [M+H] +,HPLC Method B:R T =6.81min, Purity: 90.1%. 1 H NMR(600MHz,Chloroform-d)δ 8.81(s,1H),7.86-7.84(m,1H),7.78-7.77(m,1H),7.48(s,2H),7.33(d,J=7.8Hz,1H),6.73( d,J=9.0Hz,2H),5.73-5.67(m,1H),5.04(d,J=10.2Hz,1H),4.94(d,J=16.8Hz,1H),4.74(d,J= 6.0Hz,2H),4.62-4.60(m,1H),4.54-4.52(m,1H),3.99(s,1H),3.92(d,J=4.8Hz,2H),3.64(d, J=10.8Hz,2H),3.39(d,J=10.8Hz,2H),2.78-2.70(m,3H),1.68(d,J=8.4Hz,1H),1.58(s,6H).

[0087] <Example 49: Synthesis of Compound 49> TIFF2025503478000136.tif51170 Step 1: Synthesis of compound 49-1 In a dry one-neck flask, substrate 27-2 (100 mg, 456.12 μmol) was added and dissolved in N,N-dimethylformamide (2 mL), cyclobutyl bromo (92.37 mg, 684.18 μmol), potassium carbonate (158 mg, 1.14 mmol) and potassium iodide (8 mg, 48.19 μmol) were added, and the reaction was carried out at 100° C. for 32 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 49-1 (32 mg, 117.07 μmol). LCMS (ESI) m / z: 274.2 [M+H] + . Step 2: Synthesis of compound 49-2 In a 50 mL round-bottom flask, 49-1 (32 mg, 117.07 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium carbon (10 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: Compound 49-2 (28 mg, crude). LCMS (ESI) m / z: 244.1 [M+H] + . Step 3: Synthesis of compound 49 In a dry one-neck flask, the substrate IM-6 (35.7 mg, 95.60 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (61.78 mg, 478.00 μmol) and 49-2 (25.59 mg, 105.16 μmol) were then added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 49 (20.8 mg, 33.31 μmol). LCMS (ESI) m / z: 553.2 [M+H] + ,HPLC Method B:R T =7.50min,purity:88.5%. 1 H NMR(600MHz,Chloroform-d)δ 8.82(s,1H),7.86-7.84(m,1H),7.78-7.77(m,1H),7.48(s,2H),7.33(d,J=7.8Hz,1H),6.71 (d,J=8.4Hz,2H),5.74-5.67(m,1H),5.04(d,J=10.2Hz,1H),4.94(d,J=19.4Hz,1H),4.67(d ,J=5.4Hz,2H),3.94-3.88(m,3H),3.47(d,J=10.2Hz,2H),3.35(d,J=10.2Hz,2H),3.21(s,1 H),2.81-2.72(m,1H),2.00-1.90(m,5H),1.78-1.74(m,1H),1.69-1.64(m,1H),1.58(s,6H).

[0088] <Example 50: Synthesis of Compound 50> TIFF2025503478000137.tif43170 Step 1: Synthesis of compound 50-2 In a dry one-neck flask, the substrate 50-1 (2 g, 14.91 mmol) was added and dissolved in methanol (40 mL), and formaldehyde (358.09 mg, 11.92 mmol) and acetic acid (89.51 mg, 1.49 mmol) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (15.80 g, 74.53 mmol) was added and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 50-2 (200 mg, 1.35 mmol). LCMS (ESI) m / z: 149.1 [M+H] + . Step 2: Synthesis of compound 50-3 In a dried one-neck flask under nitrogen protection, 50-2 (138 mg, 0.93 mmol), p-fluoronitrobenzene (282 mg, 1.4 mmol), Pd2(dba)3 (85 mg, 0.093 mmol), XantPhos (108 mg, 0.18 mmol), potassium tert-butoxide (358 mg, 3.72 mmol) and 1,4-dioxane (3 mL) were added. The reaction mixture was stirred under nitrogen atmosphere at 110 °C for 3 h. After completion of the reaction, which was monitored by LC-MS, it was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 50-3 (20 mg, 0.074 mmol). LCMS (ESI) m / z: 270.1 [M+H] + . Step 3: Synthesis of compound 50-4 In a 50 mL round-bottom flask, 50-3 (20 mg, 74 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium carbon (10 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 50-4 (7.80 mg, 32.59 μmol). LCMS (ESI) m / z: 240.2 [M+H]+ . Step 4: Synthesis of compound 50 In a dry one-neck flask, the substrate IM-1 (13.98 mg, 39.11 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (24.75 mg, 143.41 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (42.12 mg, 325.93 μmol) and 50-4 (7.80 mg, 32.59 μmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 50 (2 mg, 3.65 μmol). LCMS (ESI) m / z: 549.2 [M+H] + ,HPLC Method B:R T =9.17min, Purity: 95.7%. 1 H NMR(600MHz,DMSO-d6)δ 10.28(s,1H),8.87(s,1H),8.03-7.99(m,1H),7.75(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,2H), 7.61(d,J=7.8Hz,1H),7.15(d,J=8.4Hz,2H),6.70-6.60(m,2H),6.53(d,J=8.4Hz,1H),6.49- 6.42(m,1H),5.71-5.62(m,1H),5.32(s,1H),5.02-4.96(m,1H),4.85-4.79(m,1H),4.68(d,J =6.0Hz,2H),3.68-3.65(m,2H),3.30(d,J=1.8Hz,2H),2.87(s,3H),1.46(s,6H),1.24(s,1H)

[0089] <Example 51: Synthesis of Compound 51> TIFF2025503478000138.tif51170Step 1: Synthesis of compound 51-2 In a dry microwave tube, substrate 51-1 (44 mg, 195.48 μmol), IM-1-4 (44 mg, 197.96 μmol), cuprous iodide (37.70 mg, 197.96 μmol), potassium carbonate (38.3 mg, 227.14 μmol) and N,N'-dimethylethylenediamine (34.90 mg, 395.92 μmol) were added under nitrogen protection, and then 1,4-dioxane (2 mL) was added. The reaction was heated at 120 °C for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction system was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 51-2 (26 mg, 70.95 μmol). LCMS (ESI) m / z: 367.1 [M + H] + . Step 2: Synthesis of compound 51 In a dry one-neck flask, the substrate 51-2 (56 mg, 152.82 μmol) was added and dissolved in tetrahydrofuran (4 mL). Metachloroperbenzoic acid (42.06 mg, 244.52 μmol) was added and reacted at 50° C. for 2 hours, and N,N-diisopropylethylamine (98.75 mg, 764.11 μmol) and 27-4 (37.28 mg, 183.39 μmol) were added to the reaction solution and reacted at 50° C. for 16 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 51 (11 mg, 21.09 μmol). LCMS (ESI) m / z: 522.2 [M+H] + ,HPLC Method B:R T =8.05min, purity:96.8%. 1H NMR(600MHz,DMSO-d6)δ 10.05(s,1H),8.80(s,1H),8.22(d,J=8.4Hz,1H),7.64-7.59(m,4H),6.67(d,J=8.4Hz,2H) ),6.56(d,J=3.6Hz,1H),5.75-5.65(m,1H),5.00(d,J=10.2Hz,1H),4.86(d,J=17.4Hz,1H ),4.64(s,2H),4.30-4.26(m,2H),3.57(d,J=6.0Hz,2H),3.41(d,J=10.8Hz,2H),3.25(d, J=11.4Hz,2H),2.42-2.41(m,1H),1.98(s,3H),1.52(d,J=8.4Hz,1H),1.40-1.38(m,3H).

[0090] <Example 52: Synthesis of Compound 52> TIFF2025503478000139.tif43170 Step 1: Synthesis of compound 52-2 In a dry one-neck flask, the substrate 52-1 (1 g, 3.94 mmol) was added and dissolved in N,N-dimethylformamide (10 mL), iodomethane (1.40 g, 9.84 mmol) and cesium carbonate (5.13 g, 15.74 mmol) were added, and the reaction was carried out at 50° C. for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: Compound 52-2 (1 g, 3.54 mmol). LCMS (ESI) m / z: 283.1 [M+H] + . Step 2: Compound 52-3 synthesis In a dry microwave tube, substrate 52-2 (167.55 mg, 593.88 μmol), IM-1-4 (110 mg, 494.90 μmol), cuprous iodide (9.43 mg, 49.49 μmol), potassium carbonate (95.76 mg, 692.86 μmol) and N,N'-dimethylethylenediamine (8.73 mg, 98.98 μmol) were added under nitrogen protection, and then N,N-dimethylformamide (2 mL) was added. The reaction was heated at 110 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, the reaction was monitored by LCMS, and the reaction system was cooled to room temperature, and the solvent was removed by vacuum concentration, and the residue was purified by MPLC to obtain the following: compound 52-3 (16 mg, 37.78 μmol). LCMS (ESI) m / z: 425.1 [M+H] + . Step 3: Synthesis of compound 52 In a dry one-neck flask, the substrate 52-3 (18.00 mg, 42.50 μmol) was added and dissolved in tetrahydrofuran (0.5 mL). Metachloroperbenzoic acid (11.00 mg, 63.76 μmol) was added and reacted at room temperature for 10 minutes, and N,N-diisopropylethylamine (27.47 mg, 212.52 μmol) and 27-4 (8.64 mg, 42.50 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 52 (7.2 mg, 12.44 μmol). LCMS (ESI) m / z: 579.1 [M+H] + , HPLC method BR T =7.30min,purity > 98.0%. 1H NMR(600MHz,DMSO-d6)δ 9.92(s,1H),8.77(s,1H),7.61(d,J=1.8Hz,1H),7.56(d,J=8.4Hz,1H),7.52(s,1H),7 .39(s,1H),7.19(s,1H),6.59(s,3H),5.68-5.66(m,1H),5.09(s,1H),4.93(s,1H),4.2 4(s,2H),3.81(s,3H),3.80(s,2H),3.60(s,3H),3.56(d,J=5.4Hz,2H),3.37(d,J=10. 8Hz,2H),3.24-3.18(m,2H),2.39(d,J=2.4Hz,1H),1.96(s,3H),1.50(d,J=8.4Hz,1H).

[0091] <Example 53: Synthesis of Compound 53> TIFF2025503478000140.tif83170 Step 1: Synthesis of compound 53-2 In a dry one-neck flask, the substrate 53-1 (2.1 g, 10.66 mmol) was added and dissolved in N,N-dimethylformamide (25 mL), and iodoethane (4.99 g, 31.97 mmol) and potassium carbonate (4.22 g, 31.97 mmol) were added, and the reaction was carried out at 90 ° C for 12 hours. LC-MS was used for monitoring. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: Compound 53-2 (1.38 g, 6.13 mmol). LCMS (ESI) m / z: 226.0 [M + H] + . Step 2: Synthesis of compound 53-3 In a dried one-neck flask under nitrogen protection, 53-2 (849 mg, 8.66 mmol), B(pin)2 (1.61 g, 6.35 mmol), Pd(dppf)Cl2 (236 mg, 0.29 mmol), potassium tert-butoxide (845 mg, 8.66 mmol) and 1,4-dioxane (30 mL) were added. The reaction mixture was stirred under nitrogen atmosphere at 110 °C for 16 h. After completion of the reaction, monitored by LC-MS, cooled to room temperature, extracted with ethyl acetate three times, dried the organic phase over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 53-3 (680 mg, 2.5 mmol). LCMS (ESI) m / z: 274.2 [M+H] + . Step 3: Synthesis of compound 53-4 In a dry one-neck flask, the substrate 53-3 (0.47 g, 1.73 mmol) was added and dissolved in ethanol (12 mL). 6M hydrochloric acid solution (0.3 mL, 1.73 mmol) was added and reacted at 90° C. for 7 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by MPLC to obtain compound 53-4 (180 mg, 0.95 mmol). LCMS (ESI) m / z: 192.1 [M+H] + . Step 4: Synthesis of compound 53-5 In a dry one-neck flask, the substrate 53-4 (217.99 mg, 1.15 mmol) was added and dissolved in dichloromethane (20 mL). IM-1-4 (170 mg, 764.85 μmol), pyridine (242.00 mg, 3.06 mmol), and copper acetate (277.84 mg, 1.53 mmol) were added and stirred at room temperature for 24 hours. The reaction was monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure and the residue was purified by MPLC to give the following: compound 53-5 (31 mg, 84.60 μmol). LCMS (ESI) m / z: 368.1 [M+H] + . Step 5: Synthesis of compound 53 In a dry one-neck flask, the substrate 53-5 (39 mg, 106.43 μmol) was added and dissolved in tetrahydrofuran (6 mL). Metachloroperbenzoic acid (20.20 mg, 117.07 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (137.55 mg, 1.06 mmol) and 27-4 (23.80 mg, 117.07 μmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 53 (8.3 mg, 15.91 μmol). LCMS (ESI) m / z: 523.3 [M+H] + ,HPLC Method B:R T =7.18min, purity: 98.3%. 1 H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.80(s,1H),8.14(s,1H),7.92(d,J=8.4Hz,1H),7.80(s,1H),7.56-7.43(m, 2H),7.28(s,1H),6.60(s,2H),5.76-5.62(m,1H),5.08(d,J=10.2Hz,1H),4.95(d,J=17.4Hz ,1H),4.51-4.47(m,2H),4.35(s,1H),3.56(d,J=5.4Hz,2H),3.38(d,J=10.8Hz,2H),3.22( d,J=11.2Hz,2H),2.45-2.38(m,1H),1.96(s,3H),1.50(d,J=8.4Hz,1H),1.44-1.37(m,3H).

[0092] <Example 54: Synthesis of Compound 54> TIFF2025503478000141.tif67149Step 1: Synthesis of compound 54-2 In a dry one-neck flask, the substrate 54-1 (300 mg, 1.60 mmol) was added and dissolved in tetrahydrofuran (3 mL), and N,N'-carbonyldiimidazole (344.52 mg, 2.39 mmol) was added and reacted at 80 ° C for 2 hours. LC-MS was used for monitoring. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: Compound 54-2 (260 mg, 1.22 mmol). LCMS (ESI) m / z: 213.9 [M+H] + . Step 2: Synthesis of compound 54-3 In a dry one-neck flask, the substrate 54-2 (620 mg, 2.90 mmol) was added and dissolved in N,N-dimethylformamide (6 mL), and iodoethane (451.83 mg, 2.90 mmol) and cesium carbonate (1.12 g, 3.19 mmol) were added, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the following: Compound 54-3 (279 mg, 1.15 mmol). LCMS (ESI) m / z: 242.0 [M+H] + . Step 3: Synthesis of compound 54-4 In a dried one-neck flask under nitrogen protection, 54-3 (220 mg, 908.83 μmol), B(pin)2 (346.18 mg, 1.36 mmol), Pd(dppf)Cl2·dichloromethane (74.22 mg, 90.88 μmol), potassium carbonate (408.20 mg, 2.95 mmol) and 1,4-dioxane (7 mL) were added. The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. After completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 54-4 (140 mg, 484.20 μmol). LCMS (ESI) m / z: 290.2 [M+H] + . Step 4: Synthesis of compound 54-5 In a dry one-neck flask, the substrate 54-4 (140 mg, 484.20 μmol) was added and dissolved in acetonitrile (2 mL). 6M hydrochloric acid solution (80.70 μL) was added and the reaction was carried out at 80° C. for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by MPLC to obtain compound 54-5 (33 mg, 159.43 μmol). LCMS (ESI) m / z: 208.1 [M+H] + . Step 5: Synthesis of compound 54-6 In a dry one-neck flask, the substrate 54-5 (30 mg, 144.93 μmol) was added and dissolved in dichloromethane (3 mL). IM-1-4 (32.2 mg, 222.27 μmol), pyridine (11.46 mg, 144.93 μmol), and copper acetate (52.65 mg, 289.87 μmol) were added and stirred at room temperature for 24 hours. The reaction was monitored by LC-MS. After completion of the reaction, it was concentrated under reduced pressure and the residue was purified by MPLC to give the following: compound 54-6 (30 mg, 78.24 μmol). LCMS (ESI) m / z: 384.1 [M+H] + . Step 6: Synthesis of compound 54 In a dry one-neck flask, the substrate 54-6 (30 mg, 78.24 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (20.25 mg, 117.36 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (50.56 mg, 391.21 μmol) and 27-4 (19.09 mg, 93.89 μmol) were added to the reaction solution and reacted at room temperature for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 54 (4.3 mg, 6.99 μmol). LCMS (ESI) m / z: 539.1 [M+H] + ,HPLC Method A:R T =7.01min, purity:89.4%. 1H NMR(600MHz,DMSO-d6)δ 10.01(s,1H),8.79(s,1H),7.53-7.48(m,4H),7.26-7.24(m,1H),6.63-6.62(m,2H), 5.71-5.66(m,1H),5.08(d,J=10.2Hz,1H),4.98-4.95(m,1H),4.28-4.19(m,2H),3.89-3.86(m,2H),3.56(d,J=4.8Hz,2H) ,3.38(d,J=10.8Hz,2H),3.22(d,J=10.8Hz,2H),2.41-2.38(m,1H),1.96(s,3H),1.50(d,J=8.4Hz,1H),1.27-1.24(m,3H).

[0093] <Example 55: Synthesis of Compound 55> TIFF2025503478000142.tif85170 Step 1: Synthesis of compound 55-2 In a dry one-neck flask, the substrate 55-1 (0.83 g, 4.28 mmol) was added and dissolved in N,N-dimethylformamide (6 mL). Potassium tert-butoxide (960.29 mg, 8.56 mmol) and triphenylchloromethane (1.43 g, 5.13 mmol) were added and reacted at room temperature overnight. After completion of the reaction, the reaction was monitored by LC-MS, cooled to room temperature, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was recrystallized to obtain the following: Compound 55-2 (1.53 g, 3.51 mmol). LCMS (ESI) m / z: 437.1 [M+H] + . Step 2: Synthesis of compound 55-3 In a dry microwave tube, substrate 55-2 (0.88 g, 2.02 mmol), tetrahydropyrrole (573.81 mg, 8.07 mmol), cuprous iodide (38.41 mg, 201.70 μmol), potassium tert-butoxide (452.67 mg, 4.03 mmol) and 2-acetylcyclohexanone (56.55 mg, 403.40 μmol) were added under nitrogen protection, and then N,N-dimethylformamide (5 mL) was added. The reaction was carried out for 24 hours under nitrogen atmosphere at 80°C. After completion of the reaction, the reaction system was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 55-3 (250 mg, 658.77 μmol). LCMS (ESI) m / z: 380.2 [M+H] + . Step 3: Synthesis of compound 55-4 In a dry one-neck flask, 55-3 (140 mg, 368.91 μmol) was added and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. After the raw material was consumed by monitoring with LC-MS, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 55-4 (22 mg, 160.37 μmol). LCMS (ESI) m / z: 138.1 [M+H] + . Step 4: Synthesis of compound 55-5 In a dry one-neck flask, 55-4 (250 mg, 1.82 mmol) was dissolved in dimethyl sulfoxide (5 mL), and p-fluoronitrobenzene (282.85 mg, 2.00 mmol) and potassium carbonate (2.52 g, 18.22 mmol) were added in sequence. The reaction mixture was stirred at 100° C. for 12 hours. After completion of the reaction, monitored by LC-MS, it was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 55-5 (200 mg, 774.37 μmol). LCMS (ESI) m / z: 259.1 [M+H] + . Step 5: Synthesis of compound 55-6 In a dry one-neck flask, 55-5 (9 mg, 34.85 μmol) was dissolved in tetrahydrofuran (0.5) and acetic acid (0.1 mL) solution, zinc powder (45.57 mg, 696.93 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was monitored by LC-MS, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the following: compound 55-6 (6 mg, 26.28 μmol). LCMS (ESI) m / z: 229.2 [M+H] + . Step 6: Synthesis of compound 55 In a dry one-neck flask, the substrate IM-1 (42.27 mg, 118.27 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (30.61 mg, 177.40 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (76.43 mg, 591.35 μmol) and 55-6 (27 mg, 118.27 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 55 (2 mg, 3.72 μmol). LCMS (ESI) m / z: 538.2 [M+H] + , HPLC method BR T =8.23min,purity > 97.9%. 1 H NMR(600MHz,DMSO-d6)δ 10.39(s,1H),8.90(s,1H),8.10(s,1H),7.82(d,J=8.4Hz,2H),7.78-7. 77(m,2H),7.74-7.69(m,2H),7.64(d,J=7.8Hz,1H),7.35(s,1H),5.72-5 .64(m,1H),5.34(s,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.4Hz,1H), 4.69(d,J=6.0Hz,2H),3.08-3.06(s,4H),1.92-1.89(m,4H),1.47(s,6H)

[0094] <Example 56: Synthesis of Compound 56> TIFF2025503478000143.tif50170Step 1: Synthesis of compound 56 In a dry one-neck flask, the substrate 52 (2 mg, 3.46 μmol) was added and dissolved in methanol (1 mL). 1M NaOH solution (5 μl, 5.18 μmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction was monitored by LC-MS, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (basic) to obtain the following: Compound 56 (1.2 mg, 2.13 μmol). LCMS (ESI) m / z: 565.3 [M+H] + , HPLCRt=4.68min, purity > 83.3%. 1 H NMR(600MHz, methanol-d4)δ 8.65(s,1H),7.60(d,J=2.1Hz,1H),7.37(d,J=8.6Hz,3H),7.10(s,1H),7.07(d,J=8 .2Hz,1H),6.52(d,J=14.6Hz,2H),5.67-5.59(m,1H),5.06-5.00(m,1H),4.87(d,J=1 7.4Hz,1H),4.26(d,J=5.5Hz,2H),3.73(s,3H),3.57(s,2H),3.50(d,J=2.8Hz,2H),3 .39(d,J=11.0Hz,2H),2.46(s,1H),1.84(s,2H),1.79(s,3H),1.27(d,J=2.9Hz,1H).

[0095] <Example 57: Synthesis of Compound 57> TIFF2025503478000144.tif46170 Step 1: Compound 57-2 synthesis In a dry microwave tube, substrate 57-1 (546.59 mg, 2.39 mmol), IM-1-4 (444 mg, 2.00 mmol), cuprous iodide (762 mg, 4.00 mmol), potassium carbonate (552 mg, 2.00 mmol) and N,N'-dimethylethylenediamine (705 mg, 2.00 mmol) were added under nitrogen protection, and then 1,4-dioxane (10 mL) was added. The reaction was heated at 110 °C under nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction was monitored by LCMS, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 57-2 (140 mg, 377.94 μmol). LCMS (ESI) m / z: 371.1 [M + H] + . Step 2: Synthesis of compound 57 In a dry one-neck flask, the substrate 57-2 (7.4 mg, 19.98 μmol) was added and dissolved in tetrahydrofuran (0.5 mL). Metachloroperbenzoic acid (7.64 mg, 44.27 μmol) was added and reacted at room temperature for 10 minutes, and N,N-diisopropylethylamine (5.72 mg, 44.27 μmol) and 27-4 (6 mg, 29.52 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 57 (8 mg, 15.22 μmol). LCMS (ESI) m / z: 526.3 [M+H] + ,HPLC T =6.38min,purity >94.2%. 1H NMR(600MHz,DMSO-d6)δ 9.95(s,1H),8.76(s,1H),7.54(s,2H),7.38(d,J=9.0Hz,1H),7.27(d,J=8.4Hz,1H),6.99(d,J=8.5Hz,1H), 6.64(d,J=8.6Hz,2H),5.69-5.67(m,1H),5.62(d,J=18.0Hz,1H),5.10(d,J=10.2Hz,1H),4.94(d,J=17.4Hz ,1H),4.55(s,1H),4.41(d,J=9.6Hz,1H),4.36(d,J=9.6Hz,1H),4.22(s,1H),3.55(d,J=6.0Hz,2H),3.39(d ,J=11.2Hz,2H),3.22(d,J=11.2Hz,2H),2.43-2.38(m,1H),1.96(s,3H),1.57(s,3H),1.50(d,J=8.4Hz,1H).

[0096] <Example 58: Synthesis of Compound 58> TIFF2025503478000145.tif51170Step 1: Synthesis of compound 58-1 In a dry one-neck flask, substrate 38-1 (65.29 mg, 297.82 μmol) was added and dissolved in 1,2-dichloroethane (5 mL). 3-oxetanone (108 mg, 1.5 mmol) and acetic acid (0.5 mL) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (315.60 mg, 1.49 mmol) was added and reacted at room temperature for 10 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by MPLC to obtain the following: compound 58-1 (60 mg, 217.94 μmol). LCMS (ESI) m / z: 276.1 [M+H] + . Step 2: Synthesis of compound 58-2 In a 50 mL round-bottom flask, 58-1 (60 mg, 217.94 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 58-2 (45 mg, 183.43 μmol). LCMS (ESI) m / z: 246.2 [M+H] + . Step 3: Synthesis of compound 58 In a dry one-neck flask, the substrate IM-6 (41.84 mg, 112.04 μmol) and tetrahydrofuran (2 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (72.40 mg, 560.20 μmol) and 58-2 (30.23 mg, 123.24 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 58 (35 mg, 62.16 μmol). LCMS (ESI) m / z: 555.2 [M+H] + ,HPLC Method B:R T =6.27min, Purity: 98.5%. 1 H NMR(600MHz,DMSO-d6)δ 10.10(s,1H),8.80(s,1H),8.03(s,1H),7.77(s,1H),7.61-7.47(m,3H),6.67(d,J=7.8Hz,2H),5.70-5.63(m,1H) ,5.32(s,1H),4.99(d,J=10.2Hz,1H),4.83(d,J=16.8Hz,1H),4.68(d,J=2.4Hz,2H),4.58-4.56(m,2H),4.28-4.26 D2O: 1H NMR(600MHz,DMSO-d6)δ 8.81(s,1H),8.04(s,1H),7.75(s,1H),7.62-7.45(s,3H),6.69(d,J=8.4Hz,2H), 5.70-5.63(m,1H),5.03(d,J=10.2Hz,1H),4.83(d,J=16.8Hz,1H),4.69(d,J=3.0 Hz,2H),4.60-4.58(m,2H),4.32-4.29(m,2H),3.76(d,J=5.4Hz,2H),3.63-3.62( m,1H),3.26-3.24(m,4H),2.52-2.51(m,1H),1.53(d,J=8.4Hz,1H),1.48(s,6H).

[0097] <Example 59: Synthesis of Compound 59> TIFF2025503478000146.tif98170 Step 1: Synthesis of compound 59-1 In a dry one-neck flask, the substrate 46-6 (250 mg, 975.27 μmol) was added and dissolved in methanol (2 mL). Formaldehyde (16 mg, 469.76 μmol) and acetic acid (0.5 mL) were added and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (306.43 mg, 4.88 mmol) was added and reacted at 50° C. for 2 hours. TLC was monitored. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the following: Compound 59-1 (130 mg, 480.83 μmol). LCMS (ESI) m / z: 262.2 [M+H] + . Step 2: Synthesis of compound 59-2 In a dry one-neck flask, 59-1 (54 mg, 199.73 μmol) was added and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. After monitoring by LC-MS and disappearance of the raw material, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 59-2 (30 mg, 176.21 μmol). Step 3: Synthesis of compound 59-3 In a dry one-neck flask, 59-2 (30 mg, 176.21 μmol) was dissolved in dimethyl sulfoxide (2 mL), followed by p-fluoronitrobenzene (24.86 mg, 176.21 μmol) and NaH (21.15 mg, 881.05 μmol). The reaction mixture was stirred at 100° C. for 3 hours. After completion of the reaction, monitored by LC-MS, quenched with water and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 59-3 (35 mg, 120.13 μmol). LCMS (ESI) m / z: 234.1 [M+H] + . Step 4: Synthesis of compound 59-4 In a 50 mL round-bottom flask, 59-3 (35 mg, 120.13 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 59-4 (30 mg, 114.78 μmol). LCMS (ESI) m / z: 262.2 [M+H] + . Step 5: Synthesis of compound 59 In a dry one-neck flask, the substrate IM-6 (42.86 mg, 114.78 μmol) and tetrahydrofuran (2 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (74.17 mg, 573.92 μmol) and 59-4 (30 mg, 114.78 μmol) were then added and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 59 (3 mg, 4.75 μmol). LCMS (ESI) m / z: 571.2 [M+H] + ,HPLC Method B:R T =7.61min, Purity: 90.3%. 1H NMR(600MHz,Chloroform-d)δ 8.82(s,1H),7.89-7.76(m,2H),7.45-7.44(m,2H),7.35(d,J=7.8Hz,1H) ,6.97(s,2H),5.73-5.67(m,1H),5.04(d,J=10.2Hz,1H),4.94(d,J=16.8 ,1.2Hz,1H),4.74(d,J=6.0Hz,2H),3.97-3.83(m,3H),3.25-3.11(m,3H) ,2.58-2.33(m,6H),1.93(s,1H),1.78(s,1H),1.61(s,3H),1.58(s,6H).

[0098] <Example 60: Synthesis of Compound 60> TIFF2025503478000147.tif46170 Step 1: Synthesis of compound 60-1 In a dry one-neck flask, IM-1-5 (250 mg, 1.16 mmol) was dissolved in tetrahydrofuran (2 mL), the temperature was lowered to 0° C., NaH (83.30 mg, 3.47 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes. Iodomethane (492.7 mg, 3.47 mmol) was added, the mixture was warmed to room temperature, and the mixture was stirred for 6 hours. After completion of the reaction, which was monitored by LC-MS, the mixture was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to give: Compound 60-1 (210 mg, 912.64 μmol). LCMS (ESI) m / z: 230.1 [M+H] + . Step 2: Synthesis of compound 60-2 In a dry microwave tube, substrate 60-1 (207.05 mg, 899.82 μmol), IM-1-4 (200 mg, 899.82 μmol), cuprous iodide (342.74 mg, 1.80 mmol), potassium carbonate (174.10 mg, 1.26 mmol) and N,N'-dimethylethylenediamine (705 mg, 2.00 mmol) were added under nitrogen protection, and then 1,4-dioxane (4 mL) was added. The reaction was heated at 110 ° C under nitrogen atmosphere for 2 hours. After the reaction was completed by monitoring with LC-MS, the reaction system was cooled to room temperature, ammonia water (2 mL) was added, and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 60-2 (80 mg, 215.37 μmol). LCMS(ESI)m / z:372.2[M+H] + . Step 3: Synthesis of compound 60 In a dry one-neck flask, substrate 60-2 (46 mg, 123.84 μmol) was added and dissolved in tetrahydrofuran (0.5 mL). Metachloroperbenzoic acid (32 mg, 185.76 μmol) was added and reacted at room temperature for 10 minutes, and N,N-diisopropylethylamine (80.02 mg, 619.19 μmol) and 27-4 (30.21 mg, 148.60 μmol) were added to the reaction solution and reacted at room temperature for 6 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 60 (14.08 mg, 26.74 μmol). LCMS (ESI) m / z: 527.2 [M+H] + ,HPLC Method B:R T =5.86min, purity: 97.6%. 1H NMR(600MHz,DMSO-d6)δ 10.10(s,1H),8.80(s,1H),8.07-8.05(m,1H),7.83-7.82(m,1H),7.59(s,2H),7.46(d ,J=7.8Hz,1H),6.72(d,J=7.8Hz,2H),5.70-5.63(m,1H),4.99(d,J=10.2Hz,1H),4.84- 4.81(m,1H),4.69(d,J=4.2Hz,2H),3.59(d,J=3.6Hz,2H),3.43(d,J=10.8Hz,2H),3.28(d, J=10.8Hz,2H),3.09(s,3H),2.43(s,1H),1.99(s,3H),1.54(d,J=7.8Hz,1H),1.49(s,6H).

[0099] <Example 61: Synthesis of Compound 61> TIFF2025503478000148.tif44170 Step 1: Synthesis of compound 61-2 In a dry one-neck flask, the substrate 61-1 (200 mg, 1.30 mmol) was added and dissolved in N,N-dimethylformamide (2.5 mL), and iodoethane (406.24 mg, 2.60 mmol) and potassium carbonate (5.4 g, 3.91 mmol) were added, and the reaction was carried out at 75° C. for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 61-2 (140 mg, 770.83 μmol). LCMS (ESI) m / z: 266.2 [M+H] + . Step 2: Synthesis of compound 61-3 In a dry one-neck flask, substrate 61-2 (130 mg, 715.77 μmol) was added and dissolved in acetonitrile (2 mL), trimethylbromosilane (109.58 mg, 715.77 μmol) was added, and the reaction was carried out at 90° C. for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by MPLC to obtain compound 61-3 (60 mg, 265.40 μmol). LCMS (ESI) m / z: 266.2 [M+H] + . Step 3: Synthesis of compound 61-4 In a dry microwave tube, substrate 61-3 (36.99 mg, 163.60 μmol), IM-1-4 (40 mg, 179.96 μmol), cuprous iodide (62.32 mg, 327.21 μmol), potassium carbonate (31.65 mg, 229.05 μmol) and N,N'-dimethylethylenediamine (57.69 mg, 654.42 μmol) were added under nitrogen protection, followed by 1,4-dioxane (4 mL). The reaction was heated at 110 °C under nitrogen atmosphere for 3 hours. After completion of the reaction, monitored by LCMS, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by MPLC to give compound 61-4 (19 mg, 51.71 μmol). Step 4: Synthesis of compound 61 In a dry one-neck flask, substrate 61-4 (19 mg, 51.71 μmol) was added and dissolved in tetrahydrofuran (0.7 mL). Metachloroperbenzoic acid (13.39 mg, 77.57 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (33.42 mg, 258.55 μmol) and 27-4 (10.51 mg, 51.71 μmol) were added to the reaction solution and reacted at room temperature for 10 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 61 (3.89 mg, 7.44 μmol). LCMS (ESI) m / z: 523.3 [M+H] + ,HPLC Method A:R T =4.98min, Purity: 98.6%. 1H NMR (600MHz, CDCl3) δ 8.76(s,1H),8.05(d,J=8.4Hz,1H),7.89(s,1H),7.78(d,J=8.4Hz,1H),7.44(s ,2H),6.67(d,J=8.4Hz,2H),5.63-5.59(m,1H),4.93-4.90(m,3H),4.87-4.84( m,1H),4.46-4.42(m,2H),3.95(s,2H),3.58(d,J=8.4Hz,2H),3.46(d,J=8.4Hz ,2H),2.93-2.87(m,1H),2.25(s,3H),1.71(d,J=6.0Hz,1H),1.61-1.59(m,3H).

[0100] <Example 62: Synthesis of Compound 62> TIFF2025503478000149.tif57170Step 1: Synthesis of compound 62 In a dry microwave tube, substrate 62-1 (36.99 mg, 163.60 μmol), 62-2 (40.39 mg, 123.75 μmol), cuprous iodide (47.14 mg, 247.50 μmol), potassium carbonate (68.41 mg, 495.01 μmol) and N,N'-dimethylethylenediamine (21.78 mg, 247.50 μmol) were added under nitrogen protection, followed by 1,4-dioxane (2 mL). The reaction was heated at 110 °C under nitrogen atmosphere for 16 hours. After completion of the reaction, monitored by LC-MS, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by MPLC to give compound 62 (0.7 mg, 1.23 μmol). LCMS (ESI) m / z: 569.3 [M+H] + ,HPLC Method A:R T =6.03min,purity:73.2%. 1H NMR(600MHz,DMSO-d6)δ 8.93-8.92(m,1H),8.07-8.03(m,1H),7.92-7.87(m,4H),7.88(d,J=7.8Hz,1H),7.72(d, J=7.8Hz,1H), 5.76-5.71(m,1H),5.03-5.01(m,1H),4.92-4.89(m,1H),4.83-4.82(m,2H ),4.66-4.63(m,1H),4.43-4.41(m,1H),4.29-4.26(m,1H),3.57(d,J=11.4Hz,2H),3.04 -3.00(m,2H),2.95(s,3H),2.19(d,J=14.4Hz,1H),2.16-1.51(m,4H),1.58-1.53(m,7H)

[0101] <Example 63: Synthesis of Compound 63> TIFF2025503478000150.tif48170Step 1: Synthesis of compound 63-2 In a dry one-neck flask, substrate 38-1 (44 mg, 200.69 μmol) was added and dissolved in 1,2-dichloroethane (5 mL). 63-1 (171.79 mg, 1.00 mmol) and acetic acid (0.5 mL) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (211.94 mg, 1 mmol) was added and reacted at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure and the residue was purified by MPLC to obtain the following: compound 63-2 ((350 mg, 934.75 μmol). LCMS (ESI) m / z: 375.2 [M+H] + . Step 2: Synthesis of compound 63-3 In a dry one-neck flask, 63-2 (60 mg, 160.24 μmol) was added and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. After the raw material was consumed by monitoring with LC-MS, the solvent was removed by distillation under reduced pressure to obtain the following: Compound 63-3 (43 mg, 156.75 μmol). LCMS (ESI) m / z: 275.2 [M+H] + . Step 3: Synthesis of compound 63-4 In a dry one-neck flask, the substrate 63-3 (43 mg, 156.75 μmol) was added and dissolved in methanol (3 mL), and formaldehyde (26.69 mg, 783.76 μmol) and acetic acid (0.2 mL) were added and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (19.70 mg, 313.51 μmol) was added and reacted at 50° C. for 6 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the following: compound 63-4 (35 mg, 121.38 μmol). LCMS (ESI) m / z: 289.2 [M+H] + . Step 4: Synthesis of compound 63-5 In a 50 mL round-bottom flask, 63-4 (35 mg, 120.13 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 63-5 (28 mg, 71.90 μmol). LCMS (ESI) m / z: 259.2 [M+H] + . Step 5: Synthesis of compound 63 In a dry one-neck flask, the substrate IM-6 (16.89 mg, 65.36 μmol) and tetrahydrofuran (2 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (42.24 mg, 326.82 μmol) and 63-5 (28 mg, 71.90 μmol) were added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 63 (11 mg, 18.49 μmol). LCMS (ESI) m / z: 568.4 [M+H] + ,HPLC Method B:R T =5.21min, Purity: 97.5%. 1H NMR(600MHz,DMSO-d6)δ 8.82-8.79(m,1H),7.99-7.91(m,1H),7.79-7.71(m,1H),7.59-7.55(m,1H),7.51 -7.47(m,2H),6.71-6.69(m,2H),5.71-5.69(m,1H),5.67-5.61(m,1H),5.00-4.9 8(m,1H),4.83-4.56(m,3H),4.25-4.13(m,2H),4.02-3.89(m,4H),3.75-3.57(m, 5H),3.28-3.21(m,3H),,2.42-2.38(m,1H),1.80-1.72(m,1H),1.46-1.42(m,6H). D2O: 1 H NMR(600MHz,333K,DMSO-d6)δ 8.77(s,1H),7.94(s,1H),7.74(s,1H),7.57(d,J=7.2Hz,1H),7.47(s,2H),6.72(d,J=9.0Hz,2H),5.68-5.62(m,1H),5.00(d,J=10.2Hz ,1H),4.85(d,J=17.4Hz,1H),4.67(s,2H),4.17-3.62(m,10H),3.39-3.37(m,1H),3.18(s,3H),2.45(s,1H),1.77(s,1H),1.47(s,6H).

[0102] <Example 64: Synthesis of Compound 64> TIFF2025503478000151.tif54170 Step 1: Synthesis of compound 64-1 In a dry one-neck flask, substrate 38-1 (109 mg, 497.17 μmol) was added and dissolved in acetone (3 mL), and allyl bromide (90.1 mg, 745.76 μmol) and potassium carbonate (207 mg, 745.76 μmol) were added, and the reaction was carried out at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by MPLC to obtain compound 64-1 (128 mg, 497.03 μmol). LCMS (ESI) m / z: 260.2 [M+H] + . Step 2: Synthesis of compound 64-2 In a dry one-neck flask, 64-1 (128 mg, 497.03 μmol) was added and dissolved in ethanol (10 mL). Iron powder (138.92 mg, 2.49 mmol) and ammonium chloride (399 mg, 7.46 mmol) were added, and the reaction was warmed to 80° C. and stirred for 2 h. It was monitored by LC-MS. After completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to give: compound 64-2 (25 mg, 109.02 μmol). LCMS (ESI) m / z: 230.2 [M+H] + . Step 3: Synthesis of compound 64 In a dry one-neck flask, the substrate IM-1 (18 mg, 50.36 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (13 mg, 137.36 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (9.7 mg, 75.05 μmol) and 64-2 (21 mg, 91.58 μmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 64 (6.2 mg, 11.51 μmol). LCMS (ESI) m / z: 539.2 [M+H] + ,HPLC Method B:R T =5.59min, Purity: 92.7%. 1 H NMR (400MHz, DMSO-d6) δ 8.80(s,1H),8.05-8.03(m,1H),7.79-7.77(m,2H),7.61(d,J=7.8Hz,3H),6.72( d,J=8.4Hz,2H),6.01-5.72(m,1H),5.72-5.54(m,1H),5.25-4.96(m,4H),4.83( d,J=17.4Hz,1H),4.68(d,J=6.0Hz,2H),3.44(d,J=11.2Hz,2H),3.30(d,J=11.2 Hz,2H),3.18(s,2H),2.93(d,J=6.0Hz,2H),1.55(d,J=8.4Hz,1H),1.47(s,6H).

[0103] <Example 65: Synthesis of Compound 65> TIFF2025503478000152.tif50170Step 1: Synthesis of compound 65-1 In a dry one-neck flask, substrate 38-1 (87 mg, 396.83 μmol) was added and dissolved in acetone (3 mL), and iodoethane (92.84 mg, 595.25 μmol) and potassium carbonate (83 mg, 1.19 mmol) were added, and the reaction was carried out at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by MPLC to obtain compound 65-1 (87 mg, 351.81 μmol). LCMS (ESI) m / z: 248.1 [M+H] + . Step 2: Synthesis of compound 65-2 In a 50 mL round-bottom flask, 65-1 (94 mg, 380.12 μmol) was added and dissolved in methanol (5 mL). A catalytic amount of palladium on carbon (10 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 65-2 (80 mg, 368.14 μmol). LCMS (ESI) m / z: 218.2 [M+H] + . Step 3: Synthesis of compound 65 In a dry one-neck flask, the substrate IM-1 (18 mg, 50.36 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (13 mg, 137.36 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (9.7 mg, 75.05 μmol) and 65-2 (19.9 mg, 91.58 μmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 65 (6.2 mg, 11.77 μmol). LCMS (ESI) m / z: 527.2 [M+H] + ,HPLC Method B:R T =6.27min,purity:76.2%. 1H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),8.80(s,1H),8.06-8.02(m,1H),7.76(d,J=8.0Hz,1H),7.60(d,J=7.6Hz,3H),6 .70(d,J=8.4Hz,2H),5.74-5.55(m,1H),5.31(s,1H),5.04-4.94(m,1H),4.83(d,J=17.2Hz,1 H),4.68(d,J=6.0Hz,2H),3.67(d,J=5.6Hz,2H),3.42(d,J=11.2Hz,2H),3.26(d,J=11.2Hz,2 H),2.42(d,J=6.8Hz,1H),2.28(d,J=7.2Hz,2H),1.55(s,1H),1.46(s,6H),0.93-0.91(m,3H).

[0104] <Example 66: Synthesis of Compound 66> TIFF2025503478000153.tif55170Step 1: Synthesis of compound 66-1 In a dry one-neck flask, substrate 38-1 (80 mg, 364.90 μmol) was added and dissolved in N,N-dimethylformamide (3 mL), 2-bromoethanol (68 mg, 544.16 μmol), potassium carbonate (99 mg, 716.35 μmol) and potassium iodide (5 mg, 30.12 μmol) were added, and the reaction was carried out at 100° C. for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 66-1 (70 mg, 265.86 μmol). LCMS (ESI) m / z: 264.1 [M+H] + . Step 2: Synthesis of compound 66-2 In a 50 mL round-bottom flask, 66-1 (70 mg, 265.86 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 66-2 (35 mg, 150 μmol). LCMS (ESI) m / z: 234.2 [M+H] + . Step 3: Synthesis of compound 66 In a dry one-neck flask, the substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (4 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 66-2 (32 mg, 57.32 μmol) were added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 66 (45 mg, 74.45 μmol). LCMS (ESI) m / z: 543.2 [M+H] + ,HPLC Method B:R T =5.69min, Purity: 97.2%. 1 H NMR(600MHz,Chloroform-d)δ 8.81(s,1H),7.87-7.84(m,1H),7.76(d,J=7.8Hz,1H),7.47(s,2H),7.34(d,J=7.8Hz,1H),6.72(d,J=9.0Hz,2 H),5.73-5.67(m,1H),5.04(d,J=10.2Hz,1H),4.94(d,J=16.8Hz,1H),4.73(d,J=6.0Hz,2H),3.97(d,J=5.4Hz,2H) ),3.67-3.63(m,4H),3.44(d,J=10.8Hz,2H),2.82-2.80(m,1H),2.64(s,2H),1.72(d,J=8.4Hz,1H),1.59(s,6H).

[0105] <Example 67: Synthesis of Compound 67> TIFF2025503478000154.tif57170Step 1: Synthesis of compound 67-1 In a dry one-neck flask, substrate 38-1 (80 mg, 364.90 μmol) was added and dissolved in N,N-dimethylformamide (3 mL), 2-bromoethyl methyl ether (76 mg, 546.80 μmol), potassium carbonate (99 mg, 716.35 μmol) and potassium iodide (5 mg, 30.12 μmol) were added, and the reaction was carried out at 100° C. for 6 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 67-1 (75 mg, 270.45 μmol). LCMS (ESI) m / z: 264.1 [M+H] + . Step 2: Synthesis of compound 67-2 In a 50 mL round-bottom flask, 67-1 (75 mg, 270.45 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 67-2 (53 mg, 214.28 μmol). LCMS (ESI) m / z: 234.2 [M+H] + . Step 3: Synthesis of compound 67 In a dry one-neck flask, the substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 67-2 (53 mg, 214.28 μmol) were then added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 67 (40 mg, 67.11 μmol). LCMS (ESI) m / z: 557.3 [M+H] + ,HPLC Method B:R T =6.43min,purity:93.4%. 1H NMR(600MHz,Chloroform-d)δ 8.82(s,1H),7.88-7.84(m,1H),7.77(d,J=8.4Hz,1H),7.46(s,2H),7.34-7.32(m,1H),6.72(d,J=8.4Hz,2 H),5.76-5.66(m,1H),5.06-5.03(m,1H),4.97-4.92(m,1H),4.74(d,J=6.0Hz,2H),3.95-3.93(m,2H),3.65(d,J=10.8Hz,2H),3 .52-3.50(m,2H),3.39(d,J=10.8Hz,2H),3.35(s,3H),2.83-2.81(m,1H),2.66-2.64(m,2H),1.68(d,J=8.4Hz,1H),1.59(s,6H).

[0106] <Example 68: Synthesis of Compound 68> TIFF2025503478000155.tif55170Step 1: Synthesis of compound 68-1 In a dry one-neck flask, acetic acid (18 mg, 299.74 μmol) and N,N-diisopropylethylamine (42.61 mg, 329.72 μmol) were dissolved in tetrahydrofuran (2 mL), the temperature was lowered to 0°C, HATU (49.93 mg, 131.39 umol) was added, and the mixture was stirred for 10 minutes. 38-1 (65.72 mg, 299.74 μmol) was added, and the mixture was stirred for 30 minutes. After the reaction was completed, the mixture was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by MPLC to give the following: Compound 68-1 (45 mg, 172.23 μmol). LCMS (ESI) m / z: 262.1 [M+H] + . Step 2: Synthesis of compound 68-2 In a 50 mL round-bottom flask, 68-1 (45 mg, 172.23 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (20 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give compound 68-2 (29 mg, 214.28 μmol). LCMS (ESI) m / z: 236.2 [M+H] + . Synthesis of compound 68 In a dry one-neck flask, the substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 68-2 (29 mg, 125.38 μmol) were then added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 68 (51.3 mg, 89.10 μmol). LCMS (ESI) m / z: 541.3 [M+H] + ,HPLC Method B:R T =6.04min, Purity: 93.9%. 1 H NMR(600MHz,Chloroform-d)δ 8.79(s,1H),7.87-7.83(m,1H),7.76(d,J=8.4Hz,1H),7.45(d,J=7.2Hz,2H),7.33(d,J=7.6Hz,1H),6.68(d,J=8.4Hz,2 H),5.75-5.65(m,1H),5.05-5.03(m,1H),4.94(d,J=17.4Hz,1H),4.74(d,J=6.0Hz,2H),4.61-4.54(m,2H),4.09(brs,1H),3.97-3.95 (m,1H),3.68-3.58(m,2H),3.43(d,J=9.0Hz,1H),2.78-2.73(m,1H),1.94(s,3H),1.79(brs,1H),1.71(d,J=8.4Hz,1H),1.59(s,6H).

[0107] <Example 69: Synthesis of Compound 69> TIFF2025503478000156.tif57170Step 1: Synthesis of compound 69-1 In a dry one-neck flask, substrate 38-1 (241.29 mg, 1.10 mmol) was added and dissolved in N,N-dimethylformamide (5 mL), methyl chloroformate (104 mg, 1.10 mmol), potassium carbonate (194 mg, 1.40 mmol) were added, and the reaction was carried out at room temperature for 5 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 69-1 (60 mg, 216.39 μmol). LCMS (ESI) m / z: 278.1 [M+H] + . Step 2: Synthesis of compound 69-2 In a 50 mL round-bottom flask, 69-1 (75 mg, 270.45 μmol) was added and dissolved in methanol (3 mL). A catalytic amount of palladium on carbon (15 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, washed twice with methanol, and the filtrate was concentrated under reduced pressure to give the following: compound 69-2 (38 mg, 153.66 μmol). LCMS (ESI) m / z: 248.1 [M+H] + . Step 3: Synthesis of compound 69 In a dry one-neck flask, the substrate IM-6 (50 mg, 128.39 μmol) and tetrahydrofuran (3 mL) were added and dissolved by stirring. N,N-diisopropylethylamine (82.97 mg, 641.97 μmol) and 69-2 (38 mg, 153.66 μmol) were then added and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 69 (35 mg, 62.88 μmol). LCMS (ESI) m / z: 557.2 [M+H] + ,HPLC Method B:R T =7.13min, Purity: 98.7%. 1H NMR(600MHz,Chloroform-d)δ 8.79(s,1H),7.87-7.84(m,1H),7.77(d,J=8.4Hz,1H),7.44(s,2H),7.33(d,J=7.2Hz,1H),6.68(d,J=8.4Hz,2 H),5.75-5.65(m,1H),5.05-5.02(m,1H),4.96-4.91(m,1H),4.74(d,J=6.0Hz,2H),4.39(d,J=5.4Hz ,2H),3.93-3.83(m,2H),3.65(s,3H),3.37(d,J=10.2Hz,2H),2.74-2.69(m,1H),1.60-1.59(m,7H).

[0108] <Example 70: Synthesis of Compound 70> TIFF2025503478000157.tif43170Step 1: Synthesis of compound 70-2 In a dry one-neck flask, 70-1 (100 mg, 507.53 μmol) was dissolved in tetrahydrofuran (3 mL), the temperature was lowered to 0° C., NaH (14.62 mg, 609.04 μmol) was added, and the mixture was stirred at 0° C. for 10 minutes. Iodoethane (94.99 mg, 609.04 μmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, which was monitored by LC-MS, it was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to give compound 70-2 (65 mg, 288.78 μmol). LCMS (ESI) m / z: 225.0 [M+H] + . Step 2: Synthesis of compound 70-3 In a dry one-neck flask, 70-2 (65 mg, 288.78 μmol) was dissolved in trifluoroacetic acid (1 mL), acetic anhydride (30.62 mg, 288.78 μmol, 0.5 mL) was added, and the mixture was heated to 70° C. and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by MPLC to give compound 70-3 (40 mg, 149.74 μmol). LCMS (ESI) m / z: 267.0 [M+H] + . Step 3: Synthesis of compound 70-4 In a dry microwave tube, substrate 70-3 (32.78 mg, 122.70 μmol), IM-1-4 (30 mg, 134.97 μmol), cuprous iodide (46.74 mg, 245.41 μmol), potassium carbonate (23.74 mg, 171.78 μmol) and N,N'-dimethylethylenediamine (43.27 mg, 490.81 μmol) were added under nitrogen protection, followed by 1,4-dioxane (2 mL). The reaction was heated at 110 °C under nitrogen atmosphere for 3 hours. After completion of the reaction, the reaction was monitored by LC-MS, cooled to room temperature, and the solvent was removed by vacuum concentration. The residue was purified by MPLC to obtain the following: compound 70-4 (33 mg, 74.26 μmol). LCMS (ESI) m / z: 409.1 [M + H] + . Step 4: Synthesis of compound 70 In a dry one-neck flask, substrate 70-4 (59.71 mg, 146.17 μmol) was added and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (45.40 mg, 263.10 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (94.45 mg, 730.83 μmol) and 1-5 (33.55 mg, 175.40 μmol) were added to the reaction solution and reacted at room temperature for 12 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 70 (23 mg, 40.40 μmol). LCMS (ESI) m / z: 552.2 [M+H] + ,HPLC Method B:R T =6.81min, Purity: 97.6%. 1H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.84(s,1H),8.64(d,,J=10.8Hz,2H),7.74(d,J=8.4Hz,1H ),7.56(s,2H),6.91-6.89(m,2H),5.71-5.66(m,1H),4.50-4.99(m,1H), 4.85(d,J=17.4Hz,1H),4.66-4.59(m,2H),4.35-4.32(m,2H),3.09-3.08 (m,4H),2.49(s,3H),2.48-2.46(m,4H),2.23(s,3H),1.47-1.45(m,3H).

[0109] <Example 71: Synthesis of Compound 71> TIFF2025503478000158.tif74170Step 1: Synthesis of compound 71-1 In a dry one-neck flask, 70-1 (600 mg, 2.67 mmol) was dissolved in 1,4-dioxane (1 mL), tribromopyridine (3.41 g, 10.66 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, monitored by LC-MS, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the following: Compound 71-1 (230 mg, 576.62 μmol). LCMS (ESI) m / z: 398.8 [M+H] + . Step 2: Synthesis of compound 71-2 In a dry one-neck flask, 71-1 (230 mg, 576.62 μmol) was dissolved in tetrahydrofuran (1.5 mL), zinc powder (45.57 mg, 696.93 μmol) and saturated ammonium chloride solution (1.5 mL) were added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was monitored by LC-MS, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: Compound 71-2 (44 mg, 182.51 μmol). LCMS (ESI) m / z: 241.0 [M+H] + . Step 3: Synthesis of compound 71-3 In a dry one-neck flask, 71-2 (250 mg, 1.16 mmol) was dissolved in tetrahydrofuran (2 mL), the temperature was lowered to 0° C., NaH (83.30 mg, 3.47 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes. Iodomethane (492.7 mg, 3.47 mmol) was added, the mixture was warmed to room temperature, and the mixture was stirred for 6 hours. After completion of the reaction, which was monitored by LC-MS, the mixture was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 71-3 (210 mg, 912.64 μmol). LCMS (ESI) m / z: 269.0 [M+H] + . Step 4: Synthesis of compound 71-4 In a dry microwave tube, substrate 71-3 (17.61 mg, 65.44 μmol), IM-1-4 (16 mg, 71.99 μmol), cuprous iodide (24.93 mg, 130.88 μmol), potassium carbonate (12.66 mg, 91.62 μmol) and N,N'-dimethylethylenediamine (23.07 mg, 261.77 μmol) were added under nitrogen protection, followed by 1,4-dioxane (1 mL). The reaction was heated at 110 °C under nitrogen atmosphere for 3 hours. After completion of the reaction, the reaction was monitored by LC-MS, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by MPLC to give compound 71-4 (2.01 mg, 4.91 μmol). LCMS (ESI) m / z: 411.2 [M+H] + . Step 5: Synthesis of Compound 71 In a dry one-neck flask, substrate 71-4 (2.01 mg, 4.91 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (1.52 mg, 8.83 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (3.17 mg, 24.54 μmol, 4.27 μL) and 1-5 (938.70 μg, 4.91 μmol) were added to the reaction solution and reacted at room temperature for 8 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 71 (2.3 mg, 3.45 μmol). LCMS (ESI) m / z: 554.3 [M+H] + ,HPLC Method B:R T =5.89min, Purity: 83.2%. 1 H NMR(600MHz,CDCL3)δ 8.77(s,1H),7.51(d,J=7.8Hz,1H),7.42(d,J=1.8Hz,2H),7.36(d,J=8.4H z,1H),6.87-6.84(m,2H),5.70-5.63(m,1H),4.99(d,J=10.2Hz,1H),4.92( d,J=16.8Hz,1H),4.63(d,J=5.4Hz,2H),3.80-3.77(m,2H),3.36-3.24(m, 4H), 2.87-2.80(m, 4H), 2.49-2.45(m, 3H), 1.36(s, 6H), 1.23-1.21(m, 3H).

[0110] <Example 72: Synthesis of Compound 72> TIFF2025503478000159.tif57170Step 1: Synthesis of compound 72-21 In a dry one-neck flask, substrate 72-1 (88 mg, 395.92 μmol) was added and dissolved in dichloromethane (20 mL). IM-1-4 (170 mg, 764.85 μmol), pyridine (0.4 mL), and copper acetate (146 mg, 803.83 μmol) were added and stirred at 30° C. for 24 hours. LC-MS was used for monitoring. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by MPLC to give compound 72-2 (28 mg, 79.00 μmol). LCMS (ESI) m / z: 354.95 [M+H] + . Step 2: Synthesis of compound 72 In a dry one-neck flask, substrate 72-2 (28 mg, 79.00 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (27.26 mg, 157.99 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (16 mg, 83.65 μmol) and 1-5 (938.70 μg, 4.91 μmol) were added to the reaction solution and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 72 (9 mg, 17.72 μmol). LCMS (ESI) m / z: 498.1 [M+H] + ,HPLC Method B:R T =8.01min, purity: 98%. 1 H NMR(400MHz,Chloroform-d)δ 8.84(s,1H),7.85-7.81(m,2H),7.48-7.41(m,5H),6.86(d,J=8.4Hz,2H),5.79-5.72(m ,1H),5.18-5.09(m,2H),4.47(d,J=6.0Hz,2H),3.32(s,4H),2.86(s,4H),2.55(s,3H).

[0111] <Example 73: Synthesis of Compound 73> TIFF2025503478000160.tif43170Step 1: Synthesis of compound 73-2 In a dry one-neck flask, substrate 73-1 (0.5 g, 3.28 mmol) was added and dissolved in acetonitrile (5 mL). Pyridine (1.5 mL) and Selectfluor reagent (1.05 g, 2.95 mmol) were added and stirred at 15° C. for 16 hours. The reaction was monitored by LC-MS. After completion of the reaction, water was added and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give compound 73-2 (112 mg, 656.62 μmol). LCMS (ESI) m / z: 171.0 [M+H] + . Step 2: Synthesis of compound 73-3 In a dry one-neck flask, 73-2 (0.112 g, 656.62 μmol) was dissolved in N,N-dimethylformamide (3 mL), the temperature was lowered to 0° C., NaH (39.40 mg, 984.93 μmol, 60% purity) was added, and the mixture was stirred at 0° C. for 30 minutes. Iodoethane (153.65 mg, 984.93 μmol, 78.79 μL) was added, the mixture was warmed to room temperature, and the mixture was stirred for 16 hours. After completion of the reaction, which was monitored by LC-MS, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 73-3 (120 mg, 604.16 μmol). LCMS (ESI) m / z: 199.2 [M+H] + . Step 3: Synthesis of compound 73-4 In a dry microwave tube, substrate 74-3 (0.04 g, 201.39 μmol), IM-1-4 (44.76 mg, 201.39 μmol), cuprous iodide (76.71 mg, 402.77 μmol), sodium iodide (60.37 mg, 402.77 μmol), potassium carbonate (69.58 mg, 503.46 μmol) and N,N'-dimethyl-1,2-cyclohexanediamine (114.58 mg, 805.54 μmol) were added under nitrogen protection, followed by phenyl methyl ether (1.5 mL). The reaction was heated in a microwave at 130 °C for 4 hours under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, water and aqueous ammonia (1 mL) were added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 73-4 (20 mg, 52.03 μmol). LCMS (ESI) m / z: 385.0 [M+H] + . Step 4: Synthesis of compound 73 In a dry one-neck flask, substrate 73-4 (20 mg, 52.03 μmol) was added and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (19.01 mg, 93.65 μmol, 85% purity) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (67.24 mg, 520.25 μmol, 90.62 μL) and 1-5 (11.94 mg, 62.43 μmol) were added to the reaction solution and reacted at room temperature for 5 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 73 (20.7 mg, 37.39 μmol). LCMS (ESI) m / z: 528.3 [M+H] + ,HPLC Method B:R T =8.09min, Purity: 95.3%. 1H NMR(600MHz,DMSO-d6)δ 10.16(s,1H),8.84(s,1H),8.32(s,1H),7.67(s,1H),7.65(d,J=8.4Hz ,1H),7.61(s,2H),6.92(d,J=8.4Hz,2H),5.74-5.68(m,1H),5.00(d,J =10.2Hz,1H),4.86(d,J=17.4Hz,1H),4.65(s,2H),4.26-4.22(m,2H),3.12-3.09(m,4H),2.47-2.45(m,4H),2.22(s,3H),1.39-1.36(m,3H).

[0112] <Example 74: Synthesis of Compound 74> TIFF2025503478000161.tif42170 Step 1: Synthesis of compound 74-2 In a dry one-neck flask, the substrate 74-1 (1.01 g, 3.99 mmol) was added and dissolved in N,N-dimethylformamide (30 mL), methyloxirane (345.57 mg, 4.79 mmol) and potassium carbonate (1.66 g, 11.98 mmol) were added, and the temperature was raised to 120 ° C. and reacted for 8 hours. LC-MS was used for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: Compound 74-2 (680 mg, 2.09 mmol). LCMS (ESI) m / z: 311.9 [M + H] + . Step 2: Synthesis of compound 74-3 In a dry one-neck flask, 74-2 (98 mg, 301.54 μmol) was dissolved in tetrahydrofuran (4 mL), the temperature was lowered to 0° C., NaH (24.12 mg, 603.08 μmol, 60% purity) was added in portions, the temperature was raised to 60° C., and the mixture was stirred for 30 hours. After completion of the reaction, which was monitored by LC-MS, the mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to give compound 74-3 (48 mg, 196.65 μmol). LCMS (ESI) m / z: 244.0 [M+H] + . Step 3: Synthesis of compound 74-4 In a dry microwave tube, substrate 74-3 (47 mg, 192.56 μmol), IM-1-4 (31.77 mg, 142.96 μmol), cuprous iodide (36.67 mg, 192.56 μmol), potassium carbonate (38.30 mg, 277.14 μmol) and N,N'-dimethylethylenediamine (33.95 mg, 385.11 μmol) were added under nitrogen protection, and then 1,4-dioxane (3 mL) was added. The reaction was heated in a microwave at 120 °C for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction was monitored by LC-MS, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: compound 74-4 (12 mg, 31.13 μmol). LCMS (ESI) m / z: 386.1 [M + H] + . Step 4: Synthesis of compound 74 In a dry one-neck flask, substrate 74-4 (12 mg, 31.13 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (21.49 mg, 124.53 μmol) was added and reacted at room temperature for 0.5 hours, and N,N-diisopropylethylamine (20.22 mg, 156.46 μmol, 27.25 μL) and 1-5 (20 mg, 104.56 μmol) were added to the reaction solution and reacted at room temperature for 8 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 74 (7.2 mg, 12.56 μmol). LCMS (ESI) m / z: 529.2 [M+H] + ,HPLC Method B:R T =7.08min, purity: 92.2%. 1 H NMR(600MHz,Chloroform-d)δ 8.80(s,1H),7.47(d,J=7.8Hz,2H),7.37-7.30(m,2H),6.90(d,J=8.4Hz,2H),5.74-5.68(m,1H),5.05(d,J=10. 2Hz,1H), 4.98(d,J=16.8Hz,1H),4.69(s,2H),4.11(s,2H),3.24(s,4H),2.69(s,4H),2.43(s,3H),1.41(s,6H).

[0113] <Example 75: Synthesis of Compound 75> TIFF2025503478000162.tif73170Step 1: Synthesis of compound 75-2 In a dry one-neck flask, the substrate 75-1 (965 mg, 5.00 mmol) was added and dissolved in N,N-dimethylformamide (20 mL), and iodoethane (383 mg, 4.70 mmol) and N,N-diisopropylethylamine (1.29 g, 10.00 mmol) were added and reacted at room temperature for 1 hour. TLC was monitored. After the reaction was completed, it was extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by column chromatography to obtain the following: Compound 75-2 (650 mg, 3.22 mmol). LCMS (ESI) m / z: 202.0 [M+H]+ . Step 2: Synthesis of compound 75-3 In a dry one-neck flask, 75-2 (308 mg, 1.53 mmol) was dissolved in tetrahydrofuran (5 mL), zinc powder (1.6 g, 24.62 mmol) and ammonium chloride (642 mg, 12.00 mmol) were added, the temperature was raised to 70 ° C, and the mixture was stirred for 3 hours. After completion of the reaction, the mixture was monitored by LC-MS, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to give the following: compound 75-3 (248 mg, 1.44 mmol). LCMS (ESI) m / z: 172.1 [M + H] + . Step 3: Synthesis of compound 75-4 In a dry one-neck flask, 75-3 (248 mg, 1.44 mmol) was dissolved in triethyl orthoacetate (4 mL) and stirred at 100° C. for 1 hour. Acetic acid (1.05 g, 17.47 mmol, 1 mL) was added and stirred for 8 hours. After the reaction was completed by monitoring with LC-MS, the temperature was lowered to room temperature, concentrated under reduced pressure, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 75-4 (220 mg, 1.12 mmol). LCMS (ESI) m / z: 196.1 [M+H] + . Step 4: Synthesis of compound 75-5 In a dry microwave tube, substrate 75-4 (64 mg, 327.12 μmol), IM-1-4 (72.71 mg, 327.12 μmol), cuprous iodide (124.60 mg, 654.23 μmol), sodium iodide (98.06 mg, 654.23 μmol), potassium carbonate (38.30 mg, 277.14 μmol) and N,N'-dimethyl-1,2-cyclohexanediamine (186.12 mg, 1.31 mmol) were added under nitrogen protection, followed by phenyl methyl ether (2 mL). The reaction was heated in a microwave at 130 °C for 10 hours under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, water and aqueous ammonia (1 mL) were added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 75-5 (15 mg, 39.32 μmol). LCMS (ESI) m / z: 382.2 [M+H] + . Step 5: Synthesis of Compound 75 In a dry one-neck flask, the substrate 75-5 (15 mg, 39.32 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (20.36 mg, 117.97 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (25.36 mg, 196.25 μmol, 34.18 μL) and 1-5 (18.77 mg, 98.12 μmol) were added to the reaction solution and reacted at room temperature for 8 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 75 (3.2 mg, 5.12 μmol). LCMS (ESI) m / z: 525.2 [M+H] + ,HPLC Method B:R T =6.16min, purity:84.0%. 1H NMR(600MHz,Chloroform-d)δ 8.84(s,1H),8.07(d,J=7.8Hz,1H),7.66(d,J=7.2Hz,1H),7.46(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),5.75-5.68(m,1H),5.00(d,J=10.2 Hz,1H),4.89(d,J=17.4Hz,1H),4.73(d,J=3.6Hz,2H),4.32-4.28(m,2H),3.25(s,4H),2.71-2.68(m,7H),2.45(s,3H),1.47-1.42(m,3H).

[0114] <Example 76: Synthesis of Compound 76> TIFF2025503478000163.tif54170Step 1: Synthesis of compound 76 In a dry one-neck flask, substrate 51-2 (26 mg, 70.95 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (35 mg, 202.82 μmol) was added and reacted at 50°C for 2 hours, and N,N-diisopropylethylamine (45.62 mg, 353.00 μmol) and IM-2 (22 mg, 108.22 μmol) were added to the reaction solution and reacted at room temperature for 8 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 76 (15 mg, 28.76 μmol). LCMS (ESI) m / z: 522.3 [M+H] + ,HPLC Method B:R T =7.68min, purity: 94.4%. 1H NMR(600MHz,Chloroform-d)δ 8.83(s,1H),8.03(d,J=7.8Hz,1H),7.53-7.43(m,3H),7.28(d,J=3.6Hz,1H),6. 54-6.52(m,3H),5.75-5.69(m,1H),5.00(d,J=10.2Hz,1H),4.90((d,J=17.4Hz,1 H),4.76(s,2H),4.34-4.28(m,3H),3.78(s,1H),3.51-3.45(m,2H),3.21(s,1H), 2.84(s,1H),2.53(s,3H),2.21(s,1H),2.06(d,J=9.6Hz,1H),1.51-1.46(m,3H).

[0115] <Example 77: Synthesis of Compound 77> TIFF2025503478000164.tif50170Step 1: Synthesis of compound 77 In a dry one-neck flask, the substrate 51-2 (26 mg, 70.95 μmol) was added and dissolved in tetrahydrofuran (2 mL). Metachloroperbenzoic acid (35 mg, 202.82 μmol) was added and reacted at 55°C for 6 hours, and N,N-diisopropylethylamine (45.62 mg, 353.00 μmol) and 77-1 (17 mg, 89.34 μmol) were added to the reaction solution and reacted at room temperature for 8 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 77 (5 mg, 9.83 μmol). LCMS (ESI) m / z: 509.6 [M+H] + ,HPLC Method B:R T =8.50min, purity:98.2%. 1H NMR(600MHz,DMSO-d6)δ 10.18(s,1H),8.87(s,1H),8.23(d,J=7.8Hz,1H),7.67(d,J=3.0Hz,3H),7.53(d,J=7.8 Hz,1H),7.16(d,J=8.4Hz,2H),6.58(d,J=3.6Hz,1H),5.74-5.68(m,1H),5.00(d,J=7.2H) z,1H),4.86(d,J=16.8Hz,1H),4.61(s,2H),4.30-4.26(m,2H),2.86(d,J=11.4Hz,2H),2 .41-2.39(m,1H),2.19(s,3H),1.97-1.93(m,2H),1.71-1.62(m,4H),1.41-1.38(m,3H).

[0116] <Example 78: Synthesis of Compound 78> TIFF2025503478000165.tif93170 Step 1: Synthesis of compound 78-1 In a dry one-neck flask, 3,4-difluoronitrobenzene (159 mg, 999.43 μmol) was dissolved in dimethyl sulfoxide (3 mL), and 27-1 (237.78 mg, 1.20 mmol) and potassium carbonate (137.92 mg, 999.43 μmol) were added in sequence. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, it was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 78-1 (302 mg, 890 μmol). LCMS (ESI) m / z: 338.2 [M+H] + . Step 2: Synthesis of compound 78-2 In a dry one-neck flask, substrate 78-1 (337.35 mg, 1 mmol) was added and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was slowly added and the reaction was carried out at room temperature for 0.5 hours and monitored by LC-MS. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain compound 78-2 (223 mg, 0.94 mmol). LCMS (ESI) m / z: 238.1 [M+H] + . Step 3: Synthesis of compound 78-3 In a dry one-neck flask, the substrate 78-2 (223 mg, 0.94 mmol) was added and dissolved in 1,2-dichloroethane (3 mL), and formaldehyde (150.13 mg, 5.00 mmol) was added and stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (1.06 g, 5.00 mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the following: Compound 78-3 (198 mg, 0.78 mmol). LCMS (ESI) m / z: 252.1 [M+H] + . Step 4: Synthesis of compound 78-4 In a dry one-neck flask, 78-3 (251.26 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and acetic acid (0.5 mL) solution, zinc powder (1.95 g, 30.00 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was monitored by LC-MS, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the following: Compound 78-4 (200 mg, 903.86 μmol). LCMS (ESI) m / z: 222.1 [M+H] + . Step 5: Synthesis of compound 78 In a dry one-neck flask, the substrate IM-1 (42.27 mg, 118.27 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (30.61 mg, 177.40 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (76.43 mg, 591.35 μmol) and 78-4 (27 mg, 118.27 μmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 78 (2 mg, 3.72 μmol). LCMS (ESI) m / z: 531.7 [M+H] + . HPLC:R T =7.53min, purity:85.0%. 1H NMR(600MHz,DMSO-d6)δ 10.28(s,1H),8.85(s,1H),8.002-7.99(m,1H),7.76(d,J=7.8Hz,1H),7.71-7.67(m,1H) ,7.63(d,J=7.8Hz,1H),7.34(d,J=8.4Hz,1H),6.95-6.91(m,1H),5.70-5.64(m,1H),5.34 (s,1H),5.00(d,J=10.2Hz,1H),4.83(d,J=17.4Hz,1H),4.68(d,J=6.0Hz,2H),3.63(d,J =11.1Hz,2H),3.50(d,J=5.9Hz,2H),3.43(s,2H),3.17(s,2H),2.04(s,3H),1.46(s,6H).

[0117] <Example 79: Synthesis of Compound 79> TIFF2025503478000166.tif87170 Step 1: Synthesis of compound 79-1 In a dry one-neck flask, 3,4-difluoronitrobenzene (354.16 mg, 2 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 27-1 (475.83 mg, 2.40 mmol) and potassium carbonate (276.00 mg, 2.00 mmol) were added in sequence. The reaction mixture was stirred at 100° C. for 1 hour. After completion of the reaction, it was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 79-1 (635 mg, 1.79 mmol). LCMS (ESI) m / z: 356.1 [M+H] + . Step 2: Synthesis of compound 79-2 In a dry one-neck flask, substrate 79-1 (635 mg, 1.79 mmol) was added and dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was slowly added and the reaction was carried out at room temperature for 0.5 hours and monitored by LC-MS. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain compound 79-2 (300 mg, 1.18 mmol). LCMS (ESI) m / z: 256.1 [M+H] + . Step 3: Synthesis of compound 79-3 In a dry one-neck flask, substrate 79-2 (150 mg, 587.73 μmol) was added and dissolved in 1,2-dichloroethane (2 mL), formaldehyde (88.24 mg, 2.94 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (622.81 mg, 2.94 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 79-3 (131 mg, 487 μmol). LCMS (ESI) m / z: 270.1 [M+H] + . Step 4: Synthesis of compound 79-4 In a dry one-neck flask, 79-3 (131 mg, 487 μmol) was dissolved in tetrahydrofuran (3 mL) and acetic acid (0.2 mL) solution, zinc powder (0.96 g, 14.61 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was monitored by LC-MS, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the following: Compound 79-4 (123 mg, 515 μmol). LCMS (ESI) m / z: 240.1 [M+H] + . Step 5: Synthesis of compound 79 In a dry one-neck flask, the substrate IM-1 (15 mg, 42.20 μmol) was added and dissolved in tetrahydrofuran (1 mL). Metachloroperbenzoic acid (14.09 mg, 84.40 μmol) was added and reacted at room temperature for 30 minutes, and N,N-diisopropylethylamine (27.27 mg, 211.00 μmol) and 79-4 (10.10 mg, 42.20 μmol) were added to the reaction solution and reacted at room temperature for 3 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 79 (1.5 mg, 2.48 μmol). LCMS (ESI) m / z: 549.3 [M+H] + . HPLC:R T =7.95min, purity:90.6%. 1H NMR(600MHz,DMSO-d6)δ 10.51(s,1H),8.95(s,1H),8.03-7.99(m,1H),7.75(d,J=12.0Hz,1H),7.67(d,J=12.0Hz,1H),7.55(d,J= 7.8Hz,1H),5.71-5.64(m,1H),5.70-5.64(m,1H),5.35(s,1H),5.01-4.98(m,1H),4.84(d,J=1.8Hz,1H),4 .80(d,J=1.8Hz,1H),4.69(d,J=8.0Hz,1H),3.62(d,J=15.6Hz,2H),3.17(d,J=10.2Hz,2H),3.05(d,J=10 .2Hz,2H),2.67(d,J=2.4Hz,1H),2.33(d,J=3.0Hz,1H),2.21(s,3H),1.80(d,J=12.0Hz,1H),1.46(s,6H).

[0118] <Example 80: Synthesis of Compound 80> TIFF2025503478000167.tif67170Step 1: Synthesis of compound 80-2 In a dry one-neck flask, substrate 80-1 (581.98 mg, 3.02 mmol) was added and dissolved in N,N-dimethylformamide (10 mL). Dimethyl malonate (436 mg, 3.30 mmol) and cesium carbonate (3 g, 9.05 mmol) were added, and the temperature was raised to 90°C and reacted for 2 hours. LC-MS was used for monitoring. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 80-2 (753 mg, 2.61 mmol). LCMS (ESI) m / z: 289.1 [M+H] + . Step 2: Synthesis of compound 80-3 In a dry one-neck flask, 80-2 (753 mg, 2.61 mmol) was dissolved in ethanol (10 mL) and acetic acid (2 mL) solution, iron powder (582.80 mg, 10.44 mmol) was added, the temperature was raised to 80 ° C, and the reaction was carried out for 2 hours. After the reaction was completed, it was monitored by LC-MS, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the following: compound 80-3 (417 mg, 1.84 mmol). LCMS (ESI) m / z: 227.1 [M + H] + . Step 3: Synthesis of compound 80-4 In a dry one-neck flask, the substrate 80-3 (45 mg, 198.57 μmol) was added, dissolved in acetonitrile (10 mL), iodomethane (0.22 g, 1.99 mmol), potassium carbonate (111 mg, 794.29 μmol) were added, and the reaction was carried out at 60° C. for 8 hours. LC-MS was used for monitoring. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the following: Compound 80-4 (15 mg, 58.90 μmol). LCMS (ESI) m / z: 255.1 [M+H] + . Step 4: Synthesis of compound 80-5 In a dry microwave tube, substrate 80-4 (15 mg, 58.90 μmol), IM-1-4 (13.09 mg, 58.90 μmol), cuprous iodide (22.43 mg, 117.80 μmol), sodium iodide (17.66 mg, 117.80 μmol), potassium carbonate (25 mg, 176.70 μmol) and N,N'-dimethyl-1,2-cyclohexanediamine (32.2 mg, 235.6 μmol) were added under nitrogen protection, followed by phenyl methyl ether (1.5 mL). The reaction was heated in a microwave at 130 °C for 4 hours under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, water and aqueous ammonia (1 mL) were added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 80-5 (10.5 mg, 23.84 μmol). LCMS (ESI) m / z: 441.1 [M+H] + . Step 5: Synthesis of Compound 80 In a dry one-neck flask, substrate 80-5 (30 mg, 68.11 μmol) was added and dissolved in tetrahydrofuran (1.5 mL). Metachloroperbenzoic acid (26.39 mg, 152.92 μmol) was added and reacted at room temperature for 1 hour, and N,N-diisopropylethylamine (19.76 mg, 152.92 μmol) and 1-5 (19.5 mg, 101.95 μmol) were added to the reaction solution and reacted at room temperature for 3 hours. The reaction was monitored by LC-MS, and after completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (basic) to obtain the following: Compound 80 (5.7 mg, 9.77 μmol). LCMS (ESI) m / z: 584.2 [M+H] + . HPLC:R T =6.37min, purity: 98.8%. 1H NMR(600MHz,DMSO-d6)δ 10.14(s,1H),8.82(s,1H),7.80(d,J=7.8Hz,2H),7.67-7.39(m,2H),6.92(d,J=8.4Hz,2H),5.66-5.63(m,1H),4.99(d,J=10.2H) z,1H),4.81(d,J=17.4Hz,1H),4.46(s,2H),3.59(s,3H),3.28(s,3H),3.10(s,4H),2.48-2.43(m,4H),2.23(s,3H),1.58(s,3H).

[0119] <Biological evaluation measurements:> Unless otherwise specified, in some biological evaluation experiments in the following examples, the compound AZD1775 was used as a control, and the structural information of AZD1775 (CAS number 955365-80-7) is as follows: TIFF2025503478000168.tif58170

[0120] <Experimental Example 1: Evaluation of compounds in the binding between Wee1 protein and Tracer 178 using TR-FRET method> First, compound solutions with different concentration gradients were prepared: Compounds were dissolved in DMSO and diluted 4-fold so that the final level of DMSO in each reaction well was 0.25%, with DMSO added as a positive control (maximum signal control) and a negative control (minimum signal control). Two parallel replicas were set up at each concentration for a total of 10 dose points. Compounds were added to 384-well plates by ECHO665, then Wee1 protein solution was added and proteins were placed in buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35) WEE1 (Thermo Fisher, Cat#PR7373A) to a final protein concentration of 15 nM. Reaction substrate Tracer 178 (Invitrogen, PV5593) and MAb Anti-GST-Eu crypate (Cisbio, 61GSTKLA) were added to 384-well plates (Corning, cat#3574), centrifuged at 1000 rpm for 1 min, and the 384-well reaction plate was placed on a thermostatic shaker for 60 min, 25 o C, 300 rpm, in which Tracer 178 and MAb Anti-GST-Eu crypate were placed in a buffer solution (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35), and the final reaction concentration of Tracer 178 was 50 nM, and the final concentration of MAb Anti-GST-Eu crypate was 2 nM, in which the negative control (minimum signal control) used the same amount of buffer instead of protein solution. After the incubation was completed, the data was read by BMG PHERAStar (fluorescence signal values ​​were read using 337 nm wavelength as excitation light, 620 nm and 665 nm wavelength values ​​as emission light). The fluorescence signal ratio was calculated: 665 / 620*1000 was taken as the final enzyme activity signal value, and the TR-FRET signal was normalized by the readings obtained in the positive control (maximum signal control) and negative control (minimum signal control) to obtain the inhibition rate of different concentrations of compounds. Furthermore, the IC50 of the inhibition of the enzyme activity of the compounds was calculated by fitting the log(inhibitor) vs. Response-Variable slope mode in GraphPad Prism 6. The fitting equation was Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)), where Y represents the known percentage remaining enzyme activity, and X represents the known compound concentration after Log. The Wee1 inhibitory activity of the example compounds was measured according to the above method, and the experimental results are shown in Table 4. The IC 50 The results are as follows: "-":I C 50 Measurements above 10 μM; "+":IC 50 Measurements below 10μM and above 1μM; 「++」:IC 50 Measurements below 1μM and above 100nM; 「+++」:IC 50 Measurements below 100nM and above 10nM; 「++++」:IC 50 Measurements below 10nM and above 5nM; 「+++++」:IC 50 Measured value is less than 5nM.

[0121] [Table 4] As can be seen from the above experiments, the compounds disclosed in the present invention have significant inhibitory activity against Wee1 kinase.

[0122] <Experimental Example 2: Cell proliferation inhibitory activity evaluation> 1. Evaluation of the antiproliferative effects of compounds on H1299 cells by Cell Titer-Glo method. H1299 (ATCC, cat#HTB-96) cells were seeded into 384-well plates (Corning, 3707) at 750 cells / well in media (90% 1640 (Hyclone, cat# 16600082) + 10% FBS (Corning, Cat# 35-081-CV) + 100ug / ml Normocin (InvivoGen, cat#Ant-nr-2)) and incubated overnight at 37°C, 5% CO2 to allow wall attachment. Different concentration gradients of compound solutions were set up. DMSO was dissolved to a concentration of 10 mM experimental compound and 10 mM reference compound AZD1775, and the compounds were serially diluted with culture medium to set up a total of 9 dose points, with 2 parallel replicates for each concentration. The cell growth group without compound was the positive control (maximum signal control), and culture medium was the negative control (minimum signal control), with the final concentration of DMSO in each reaction well being 0.2%. After removing the culture medium from the 384-well plate, 25ul of the constituent compounds with different concentrations were transferred to the well plate, and the compounds and cells were incubated in a cell culture incubator at 37°C and 5% CO2 for 3 days. The 384-well plate was removed from the cell culture incubator and equilibrated to room temperature for 1 hour, after which 25ul of Cell Titer-Glo detection reagent was added to each reaction well and dissolved by bed shaking for 2 minutes, after which the plate was incubated at room temperature for 10 minutes and read on a BMG PHERAStar (Luminescence). The inhibition rate was calculated from the luminescence signal. The average value of the positive control (maximum signal control) and the negative control (minimum signal control) was calculated first. The inhibition rate of the compounds at different concentrations was calculated by the formula 139. The IC of the compounds inhibiting the cell activity was calculated as 50 was calculated by fitting in log(inhibitor) vs. Response-Variable slope mode using GraphPad Prism 6. The fitting equation is Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)), where Y represents the inhibition rate and X represents the concentration of the known compound after log.

[0123] 2. Evaluation of the antiproliferative effects of compounds on MIA PaCa2 cells by Cell Titer-Glo method. MIA PACA2 (ATCC, cat# CRL-1420) cells were seeded into 384-well plates (Corning, 3707) at 750 cells / well in medium 90% 1640 (Hyclone, cat# 16600082) + 10% FBS (Corning, Cat# 35-081-CV) + 100ug / ml Normocin (InvivoGen, cat# Ant-nr-2)) and incubated overnight at 37°C, 5% CO2 to allow wall attachment. Different concentration gradients of compound solutions were set up. DMSO was dissolved to a concentration of 10 mM experimental compound and 10 mM reference compound AZD1775, and the compounds were serially diluted with culture medium to set up a total of 9 dose points, with 2 parallel replicates for each concentration. The cell growth group without compound was the positive control (maximum signal control), and culture medium was the negative control (minimum signal control), with the final concentration of DMSO in each reaction well being 0.2%. After removing the culture medium from the 384-well plate, 25ul of the constituent compounds with different concentrations were transferred to the well plate, and the compounds and cells were incubated in a cell culture incubator at 37°C and 5% CO2 for 3 days. The 384-well plate was removed from the cell culture incubator and equilibrated to room temperature for 1 hour, after which 25ul of Cell Titer-Glo detection reagent was added to each reaction well and dissolved by bed shaking for 2 minutes, after which the plate was incubated at room temperature for 10 minutes and read on a BMG PHERAStar (Luminescence). The inhibition rate was calculated from the luminescence signal. The average value of the positive control (maximum signal control) and the negative control (minimum signal control) was calculated first. The inhibition rate of the compounds at different concentrations was calculated by the formula 140. The IC of the compounds inhibiting the cell activity was calculated. 50was calculated by fitting in log(inhibitor) vs. Response-Variable slope mode using GraphPad Prism 6. The fitting equation is Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)), where Y represents the inhibition rate and X represents the concentration of the known compound after log.

[0124] The results of the in vitro anti-proliferation experiments of the exemplary compounds against H1299 and MIA Paca-2 cells using the above-mentioned method are shown in Table 5. The IC 50 was determined and classified as described below: "-":I C 50 Measurements above 10 μM; "+":IC 50 Measurements below 10 μM and above 5 μM; 「++」:IC 50 Measurements below 10 μM and above 2 μM; 「+++」:IC 50 Measurements below 2μM and above 1μM; 「++++」:IC 50 Measurements below 1μM and above 0.1μM; 「+++++」:IC 50 Measured value is less than 0.1μM.

[0125] [Table 5] TIFF2025503478000173.tif46170 As can be seen from Table 5, most of the compounds of the present invention have good growth inhibitory activity against H1299 and MIA PaCa-2 tumor cells, and some of them have better growth inhibitory activity than the control compound AZD1775.

[0126] <Experimental Example 3: In vitro liver microsome (mouse and human) experiment> 1. Preparation of Working Solutions Microsomes were removed from the -80°C refrigerator, thawed quickly in a 37°C water bath, and used on ice. Test substances were diluted in DMSO to prepare 10 mM stock solutions, and then diluted in acetonitrile to obtain a secondary stock solution of 0.5 mM. Microsomes were diluted to 0.75 mg / ml with Buffer C. Secondary stock solutions were added to a final concentration of 1.5 μM of compound as working solutions, and based on n=2, five time points were calculated, and 350 μL of each compound was prepared and placed on ice before use. NADPH was diluted in Buffer C to a working solution of 6 mM to obtain a starter solution. Acetonitrile solutions containing internal standards were prepared as precipitants, and verapamil-HCl was used as an internal standard at a concentration of 4 ng / ml. 2. Experimental Procedure A round-bottom well plate was prepared and recorded as the reaction plate, and the set working solution of each compound was dispensed into the well plate at 30 μL / well according to the number of replicate samples and time points (0-hour samples were also added to the reaction plate). The reaction plate was incubated at 37°C for 10 minutes. Another sharp-bottom well plate was taken and recorded as the precipitation plate, and 135 μL of precipitant was added to each well. The 0-hour samples were transferred to the precipitation plate and 15 μL of starter solution was added. The precipitation plate was placed on ice before centrifugation and set aside for use. A sufficient amount of diluted starter solution was added to the dispensing plate to facilitate aspirating the displacement gun. Reactions were performed in a heated incubator, and 15 μL of starter solution / sample was drawn up using a displacement gun and added to the reaction plate. Reactions were started with slight shaking and mixing, and a timer was used to accurately time and record the reactions. Typically, samples with shorter reaction times were started later and vice versa, to allow enough time for multiple plate runs to finish the reactions. Example: For a 5 min, 15 min, 30 min, 60 min experiment, the 60 min sample was started first and the 5 min sample was started later to allow enough time for the 5 min groups. After the reaction time, all the solution in the reaction plate was aspirated with a displacement gun and added to the precipitation plate, at which point the reaction was terminated. After all reactions were completed, the precipitation plate was shaken at 600 rpm on a plate shaker for 10 minutes to precipitate the proteins. The plate was centrifuged at maximum centrifuge speed at 4°C for 15 minutes, and 80 μL of the supernatant was taken and added to 320 μL of purified water, mixed, and analyzed by LC-MS.

[0127] 3. Experimental results: As shown in Table 6. [Table 6] As can be seen from Table 6, the compounds of the present invention have good metabolic stabilizing properties as assessed in an in vitro liver microsome model.

[0128] <Experimental Example 4: Cell permeability evaluation (Caco-2 model)> Caco-2 cells were purchased from the American Model Tissue Cell Collection (Rockville, MD). The cell culture medium was modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids. The cells were seeded onto polycarbonate filter membranes (product no. 3396) and cultured at 37°C in a 5% CO2 incubator. The cells were cultured for 21-28 days after inoculation and could be used for transit experiments, and the compaction of the cell monolayer was characterized and verified by the apparent permeability coefficient (Papp) of Lucifer Yellow. In the experiment, the compounds were dissolved in DMSO to prepare 10 mM stock solutions, and then diluted with Hanks Balanced Salt Solution (HBSS, Invitrogen, Cat# 14025-092) containing 25 mM HEPES (pH 7.4) to obtain working solutions. The working solutions of 10 μM of the test compounds were added to the apical and basolateral membrane sides of Caco-2 and incubated at 37 °C for 90 min. After incubation, the samples were diluted on the apical and basolateral membrane sides, and the compound concentrations on the apical and basolateral membrane sides were detected by LC-MS / MS, and the compound concentrations were calculated by standard curve quantification. The experimental results are shown in Table 7.

[0129] [Table 7] As can be concluded from the experimental results in Table 7, the cell permeability properties of some compounds of the present invention in the Caco-2 model are comparable to those of the control compounds.

[0130] <Experimental Example 5: Evaluation of plasma protein binding ratio (PPB)> 1. Experimental Procedure Sample preparation: Compounds were dissolved in DMSO to give a stock solution of 10 mM, then the compounds were diluted in PBS to give a secondary stock solution of 0.02 mM, which was further diluted to 1 μM with blank plasma to give the sample to be incubated. Preparation of the dialysis apparatus: Add 400 μL of blank PBS to the white wells of the equilibrium dialysis plate, add 200 μL of the plasma sample set to the red wells, and seal the dialysis plate with sealing film. Preparation of recovery plate: Two 96-well deep well plates were prepared and labeled T0 and T5. All plasma samples were added to the two plates with n = 2. 300 μL of acetonitrile (verapamil-HCl, 4 ng / mL) was added directly to the T0 plate, and 50 μL of blank PBS was added and mixed for 5 minutes, then placed in a 4°C refrigerator and left for 5 minutes until the end of the incubation experiment. Experimental procedure: The dialysis device and T5 plate were incubated in a microplate incubator for 5 hours (37°C, 300 rpm or minimum rotation speed). After the incubation was completed, 300 μL of acetonitrile (verapamil-HCl, 4 ng / mL) was added, and 50 μL of PBS solution was prepared. After the dialysis was completed, a new 96-well deep well plate was taken. 50 μL of plasma well sample was taken and added to the corresponding position of the 96-well plate, then 300 μL of acetonitrile was added, and 50 μL of blank PBS was supplemented. 50 μL of buffer well sample was taken and added to the corresponding position of the 96-well plate, then 300 μL of acetonitrile was added, and 50 μL of blank plasma was supplemented. 300 μL of acetonitrile (verapamil-HCl, 4 ng / mL) was added to the plasma well of the T5 plate, the...

Claims

1. A compound represented by formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. [Among them, R １ But, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C ０～２ Alkylene groups -CN, -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ alkylene-(3- to 10-membered heterocycloalkyl group); -C ０～２ Alkylene group, -C １～６ Alkyl group, -C ２～６ Alkenyl group, -C ２～６ The alkynyl group, the 3- to 10-membered cycloalkyl group, and the 3- to 10-membered heterocycloalkyl group may further comprise one, two, three, or four independent R １１ may be substituted with R １１ is hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ selected from the group consisting of alkyl groups and halogens; R ２ is selected from the group consisting of formula 2, R ２１ is hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -C ０～２ Alkylene group -C(O)OC １～６ Alkyl group, -C ０～２ Alkylene groups -COOH, -C(O)C １～６ selected from the group consisting of alkyl groups and halogens; R ３ is selected from the group consisting of formula 3, X １ is a chemical bond, O, NR Ｎ１ or CR Ｃ１ R Ｃ２ X is selected from the group consisting of ２ But N or CR Ｃ１ X is selected from the group consisting of ３ But, O, NR Ｎ１ or CR Ｃ１ R Ｃ２ Selected from the group consisting of n is selected from the group consisting of 1, 2 or 3; R Ｎ１ is hydrogen, halogen, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C(O)(C １～６ alkyl groups), R Ｃ１ , R Ｃ２ are each independently hydrogen, halogen, a cyano group, a nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ Alkyl group) (C １～６ alkyl groups), R ４ is selected from the group consisting of -(5- to 12-membered bridged heterocycloalkyl groups), the bridged heterocycloalkyl group further comprising one, two, three or four independent R ４１ may be substituted with R ４１ is hydrogen, oxo, -C １～６ Alkyl group, -C ２～６ Alkenyl group, halogen-substituted C １～６ C substituted with alkyl or hydroxyl groups １～６ Alkyl group, halogen, cyano group, nitro group, -OH, -C ０～２ Alkylene group -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -C(O)R ４２ , -C ０～２ Alkylene group -C(O)NR ４２ R ４３ , -C ０～２ Alkylene group -C(O)OR ４２ , -C ０～２ Alkylene group -S(O)R ４２ , -C ０～２ Alkylene group -S(O)NR ４２ R ４３ , -C ０～２ Alkylene group -S(O)OR ４２ , -C ０～２ Alkylene group -S(O) ２ R ４２ , -C ０～２ Alkylene group -S(O) ２ N.R. ４２ R ４３ , -C ０～２ Alkylene group -S(O) ２ OR ４２ , -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ alkylene group-(5- to 10-membered heteroaryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, the aryl ring, and the heteroaryl ring further comprise one, two, three, or four independent R ４４ may be substituted with R ４２ , R ４３ are each independently hydrogen, halogen, a cyano group, a nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ alkylene-(5- to 10-membered heteroaryl ring); R ４４ is hydrogen, oxo, halogen, cyano group, nitro group, -OH, -C １～６ Alkyl group, halogen-substituted -C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl groups), Or, R ４１ , R Ｃ１ Or R Ｃ２ form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring together with the atom(s) directly linked thereto; R ５ is hydrogen, oxo, halogen, cyano group, nitro group, -OH, -NH ２ , -C １～６ Alkyl group, halogen-substituted C １～６ C substituted with alkyl or hydroxyl groups １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -C ０～２ Alkylene group -NH(C １～６ alkyl group), —O—C ０～２ Alkylene group -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -O-(3- to 10-membered cycloalkyl group), -O-C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ alkylene group-(5- to 10-membered heteroaryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, the aryl ring, and the heteroaryl ring further comprise one, two, three, or four independent R ５１ may be substituted with The above R ５１ is hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, oxo, halogen, cyano group, nitro group, -OH, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -C ０～２ Alkylene group -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl groups), Each R ６ are each independently hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, halogen, cyano group, nitro group, -OH, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ Alkylene group -(5-10 membered heteroaryl ring), -C ０～２ Alkylene group -(5-12 membered spiro ring), -C ０～２ Alkylene group -(5-12 membered spiro heterocycle), -C ０～２ Alkylene group -(5-12 membered bridged ring), -C ０～２ alkylene group-(5- to 12-membered bridged heterocycle), wherein ring A is selected from the group consisting of a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, and a 5- to 12-membered bridged heterocycle, wherein the spiro ring, spiro heterocycle, bridged ring, and bridged heterocycle further comprise one, two, three, or four independent R Ａ１ may be substituted with Each R Ａ１ are each independently hydrogen, halogen, a cyano group, a nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ Alkylene group -(5-10 membered heteroaryl ring), -C ０～２ Alkylene group -(5-12 membered spiro ring), -C ０～２ Alkylene group -(5-12 membered spiro heterocycle), -C ０～２ Alkylene group -(5-12 membered bridged ring), -C ０～２ alkylene group-(5- to 12-membered bridged heterocycle), wherein ring B is selected from the group consisting of a 3- to 10-membered carbocycle, a 3- to 10-membered heterocycle, a 5- to 10-membered aryl ring, a 5- to 10-membered heteroaryl ring, a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, a 5- to 12-membered bridged heterocycle, a 3- to 10-membered fused ring, and a 3- to 10-membered fused heterocycle, wherein the carbocycle, heterocycle, aryl ring, heteroaryl ring, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle, fused ring, and fused heterocycle further comprise one, two, three, or four independent R Ｂ１ may be substituted with Each R Ｂ１ are each independently hydrogen, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, halogen, cyano group, nitro group, -OH, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ alkylene-(5- to 10-membered heteroaryl ring); R ７ , R ８ are each independently hydrogen, halogen, a cyano group, a nitro group, -OH, -C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ alkylene-(5- to 10-membered heteroaryl ring); Or, R ７ , R ８ together with the atom(s) directly linked thereto form a 3- to 10-membered fused ring, a 3- to 10-membered fused heterocyclic ring, a 3- to 10-membered spiro ring, or a 3- to 10-membered spiro heterocyclic ring, and the fused ring, fused heterocyclic ring, spiro ring, or spiro heterocyclic ring further comprises one, two, three, or four independent R ７１ may be substituted with Each R ７１ are each independently hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, halogen, cyano group, nitro group, -OH, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl groups), wherein ring C is selected from the group consisting of a 5- to 12-membered spiro ring, a 5- to 12-membered spiro heterocycle, a 5- to 12-membered bridged ring, a 5- to 12-membered bridged heterocycle, a 3- to 10-membered fused ring, and a 3- to 10-membered fused heterocycle, wherein the spiro ring, spiro heterocycle, bridged ring, bridged heterocycle, fused ring, and fused heterocycle further comprise one, two, three, or four independent R Ｃ１ may be substituted with Each R Ｃ１ are each independently hydrogen, halogen, a cyano group, a nitro group, —OH, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl group), -C ０～２ Alkylene group -(3- to 10-membered cycloalkyl group), -C ０～２ Alkylene group -(3- to 10-membered heterocycloalkyl group), -C ０～２ Alkylene group -(5- to 10-membered aryl ring), -C ０～２ Alkylene group -(5-10 membered heteroaryl ring), -C ０～２ Alkylene group -(5-12 membered spiro ring), -C ０～２ Alkylene group -(5-12 membered spiro heterocycle), -C ０～２ Alkylene group -(5-12 membered bridged ring), -C ０～２ alkylene group-(5- to 12-membered bridged heterocycle), R １０ is hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ alkyl groups, R ９ But, -C ０～２ Alkylene group -C(O)NR ９１ R ９２ , -C(O)C １～６ alkyl groups, each R ９１ , R ９２ are each independently hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ alkyl groups, Or, R ９１ , R ９２ together with the atom to which they are directly attached form a 3- to 10-membered heterocyclic ring, the heterocyclic ring further comprising one, two, three or four independent R ９３ may be substituted with Each R ９３ are each independently hydrogen, C １～６ Alkyl group, halogen-substituted C １～６ Alkyl group, halogen, cyano group, nitro group, -OH, -O(C １～６ alkyl group), -O(C substituted with halogen １～６ alkyl group), -NH ２ , -NH(C １～６ alkyl group), -N(C １～６ Alkyl group) (C １～６ alkyl groups), R ３ is formula 4, ring B is a 3-membered carbocyclic ring, and R １ is formula 5, R ２ is not Equation 6, R ３ is formula 7, and R ７ , R ８ are each hydrogen, R １ is formula 8, R ２ is not Equation 9, R ３ is formula 10, and X １ is a bond, and R ４ is formula 11, and R １ is formula 12, R ２ is not Equation 13, R ３ is formula 14, and X １ is a bond, and R ４ is Formula 15, and R １ is Formula 16, R ２ is not Equation 17; R ３ is Formula 18, and R １ is formula 19, R ２ is formula 20; R ３ is formula 21, and R １ is formula 22, R ２ is not Equation 23, R ２ is Formula 24, and R ２１ is methyl, R １ is formula 25, R ３ is not Equation 26, R ２ is Formula 27, and R ２１ is hydrogen, R １ is formula 28, R ３ is not Equation 29, R ２ is Formula 30, and R ２１ is hydrogen, R １ is formula 31, R ３ is not Equation 32, R ２ is Formula 33, and R ２１ is hydrogen, R １ is formula 34, R ３ is not Equation 35, R ２ is Formula 36, ​​and R １ is formula 37, R ３ is not the formula 38.

2. R １ The compound according to claim 1, wherein is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, formula 39, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

3. R ２ The compound according to claim 1, wherein: is selected from the group consisting of formula 40, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

4. X １ is a chemical bond, O, NR Ｎ１ or CR Ｃ１ R Ｃ２ Selected from the group consisting of R Ｃ１ , R Ｃ２ are each independently hydrogen, C １～３ Alkyl group, halogen, halogen-substituted C １～３ Alkyl group, -C １～２ Alkylene group -N(C １～３ Alkyl group) (C １～３ alkyl groups), R Ｎ１ is hydrogen, C １～３ Alkyl group, halogen-substituted C １～３ The compound according to claim 1, its stereoisomer, or its pharma- ceutically acceptable salt, characterized in that it is selected from the group consisting of alkyl groups and -(3- to 10-membered heterocycloalkyl groups).

5. R ４ is selected from the group consisting of formula 41, wherein X is O, NR ４１ X is selected from the group consisting of ４ is O, NH or CH ２ n is selected from the group consisting of １ is selected from the group consisting of 1 or 2; ４ furthermore, one, two, three or four independent R ４１ may be substituted with R ４１ is hydrogen, oxo, C １～３ Alkyl group, -C ２～６ Alkenyl group, halogen-substituted C １～３ C substituted with alkyl or hydroxyl groups １～６ Alkyl group, -C ０～２ Alkylene group -O(C １～３ alkyl group), -NH ２ , -NH(C １～３ alkyl group), -N(C １～３ Alkyl group) (C １～３ alkyl group), -C(O)R ４２ , -C(O)NR ４２ R ４３ , -C(O)OR ４２ , -(3- to 10-membered cycloalkyl group), -(3- to 10-membered heterocycloalkyl group), -C １～２ alkylene group-(5- to 10-membered aryl ring), wherein the alkyl group, the alkylene group, the cycloalkyl group, the heterocycloalkyl group, and the aryl ring further comprise one, two, three, or four independent R ４４ may be substituted with R ４２ , R ４３ are each independently hydrogen, halogen, —OH, C １～３ Alkyl group, halogen-substituted C １～３ alkyl groups, R ４４ is hydrogen, C １～３ Alkyl group, halogen-substituted C １～３ Alkyl group, -O(C １～３ 5. The compound according to claim 4, its stereoisomer, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (a) aryl, (b) aryl, (c) aryl, (d) aryl, (e) aryl, (f) aryl, (g) aryl, (h) aryl, (i) aryl, (j ...

6. R ４ The compound according to claim 5, wherein: is selected from the group consisting of formula 42, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

7. R ５ is hydrogen, halogen, -C １～３ Alkyl group, halogen-substituted C １～３ C substituted with alkyl or hydroxyl groups １～３ Alkyl group, -O(C １～３ alkyl group), -NH(C １～３ alkyl group), -O-C2 alkylene group -N(C １～３ Alkyl group) (C １～３ In the above, the alkyl group, the alkylene group, the cycloalkyl group, and the heterocycloalkyl group are each independently selected from the group consisting of one, two, three, or four independent R ５１ may be substituted with R ５１ is hydrogen, C １～３ Alkyl group, halogen-substituted C １～３ 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of alkyl groups.

8. The above R ５ The compound according to claim 7, wherein is selected from the group consisting of methyl, ethyl, ethoxy, F, methyl substituted with a hydroxy group, formula 43, its stereoisomer, or its pharma- ceutically acceptable salt.

9. R ６ is hydrogen, -C １～３ Alkyl group, -NH(C １～３ alkyl group), -N(C １～３ Alkyl group) (C １～３ 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: (a) alkyl group;

10. 2. The compound of claim 1, wherein the A ring is selected from the group consisting of formula 44, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

11. Ring B is selected from the group consisting of a 3- to 10-membered heterocycle, a 5- to 12-membered bridged heterocycle, and a 3- to 10-membered fused heterocycle, wherein the heterocycle, bridged heterocycle, and fused heterocycle further comprise one, two, three, or four independent R Ｂ１ may be substituted with Each R Ｂ１ are each independently hydrogen, C １～３ Alkyl group, halogen-substituted C １～３ 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of alkyl groups.

12. 2. The compound of claim 1, wherein the B ring is selected from the group consisting of formula 45, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

13. 2. The compound according to claim 1, wherein the C-ring is selected from the group consisting of formula 46, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

14. R ７ , R ８ are each independently selected from the group consisting of formula 47; or R ７ , R ８ 2. The compound of claim 1, wherein: R is an integer from 1 to 10; ... and R is an integer from 1 to 10. The compound of claim 1, wherein: R is an integer from 1 to 10;

15. The above R ３ 49. The compound of claim 1, wherein: is selected from the group consisting of formula 49, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

16. 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that the compound described in formula 1 is: 【Table 1】

17. 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that the compound described in formula 1 is: 【Table 2】

18. 2. The compound according to claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, characterized in that the compound described in formula 1 is: 【Table 3】

19. 20. Use of a compound according to any one of claims 1 to 18, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease mediated by WEE1.

20. The use according to claim 19, characterized in that the WEE1 mediated disease is one or more diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, precancerous syndromes.

21. A pharmaceutical composition, characterized in that it is a formulation comprising a compound according to any one of claims 1 to 18, its stereoisomer, or a pharma- ceutically acceptable salt thereof as a medicament active ingredient, together with pharma- ceutically acceptable additives.

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