Small molecule compounds having phosphorylated aryl structures and uses thereof

Abstract

The present application discloses small molecule compounds having a phosphorylated aryl structure and uses thereof. The compounds provided herein or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or the pharmaceutical compositions provided in the second aspect of the present invention, effectively inhibit / block YAP-TEAD binding and inhibit / block YAP-TEAD transcriptional function by targeting the palmitoyl pocket of TEAD, thereby enabling the prevention and / or treatment of diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to a Chinese patent application filed on September 23, 2022, bearing application number 2022111702572 and entitled "Small molecule compound having phosphorylated aryl structure and use thereof," the entire text of which is incorporated herein by reference.

[0002] This patent application claims priority to a Chinese patent application filed on June 2, 2023, bearing application number 202310645010X and entitled "Small molecule compound having phosphorylated aryl structure and use thereof," the entire text of which is incorporated herein by reference. [Technical Field]

[0003] The present invention relates to the field of chemicals, and in particular to small molecule compounds having phosphorylated aryl structures and uses thereof. [Background technology]

[0004] The Hippo signaling pathway plays an important regulatory role in embryonic development, cell proliferation, wound healing, tissue regeneration, and homeostasis, and its dysfunction is one of the factors promoting the development and progression of many diseases. The Hippo signaling pathway is primarily composed of a cytoplasmic kinase module and a nuclear transcription module. YAP / TAZ acts as a link between the two and controls the onset and onset of Hippo signaling via its own phosphorylation state. When YAP / TAZ is phosphorylated by the kinase module LATS1 / 2, it remains in the cytoplasm and is degraded by the proteasome (Hippo-off). When YAP / TAZ is dephosphorylated, it is transported into the nucleus and binds to the TEAD family of transcription factors as transcriptional coactivators, significantly enhancing the transcriptional activity of TEADs and promoting proliferation (Hippo-on). Because the kinase module of the Hippo signaling pathway negatively regulates transcriptional output, conventional small molecule kinase inhibitor strategies theoretically cannot inhibit this process and may even have the opposite effect, making it unsuitable as a drug target. Current research has shown that several small molecule compounds can inhibit Hippo signaling, but most of them have unclear mechanisms, poor biological activity, and poor pharmacokinetic properties, due to the lack of drug targets and ideal small molecule binding sites in this pathway.

[0005] To address this issue, we discovered that the TEAD family of transcription factors in the Hippo signaling pathway, a transcriptional module, possesses a conserved cysteine ​​S-palmitoylation modification in their YAP-binding domain. Unlike typical protein lipid acylation, this palmitoyl 15-carbon long chain is not externally exposed to facilitate membrane localization or trafficking, but is instead buried deep within the central pocket of TEAD. Functionally, this palmitoylation stabilizes TEAD proteins and may also influence YAP-TEAD interaction and TEAD transcriptional activity. Most importantly, this palmitoyl pocket contains a tubular hydrophobic lumen and a hydrophilic branched pocket, making it an ideal binding site for small molecule drugs. Furthermore, the palmitoyl residue in TEAD is a conserved cysteine, which can be used to design covalent inhibitors.

[0006] The intractability of YAP has always posed a challenge in small molecule drug research. The discovery of the palmitoyl pocket of TEAD has opened the door to the opportunity to use small molecules to intervene in the YAP-TEAD signaling axis. That is, small molecules can bind to the palmitoyl pocket of the transcription factor TEAD, disrupting YAP-TEAD binding and inhibiting its transcriptional activity. Therefore, there is an urgent need to develop YAP-TEAD inhibitors to treat diseases caused by Hippo signaling pathway disorders and YAP1 overactivation and to address the issues of drug resistance and relapse associated with existing disease treatments. Summary of the Invention

[0007] It is an object of the present invention to provide a class of small molecule compounds having polysubstituted phosphorylated aryl structures, or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof.

[0008] Another object of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0009] Another object of the present invention is to provide uses of the above compounds or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof.

[0010] In order to solve the above technical problems, in a first aspect, the present invention provides a compound having a structure represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: TIFF2025530470000002.tif43170

[0011] wherein Z is -CH2-, -NH(CH2)n-, -O(CH2)n-, -S-, -SO-, or -SO2-, and each n is independently an integer from 0 to 3; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, at least one hydrogen is R 1-1 C replaced with 1-6 Alkyl, at least one hydrogen is R 1-1 C replaced with 2-6 is alkenyl; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, at least one hydrogen is R 1-1 C replaced with 1-6 Alkyl, at least one hydrogen is R 1-1 C replaced with 2-6 is alkenyl; Or, R 1 and R 2 are bonded to form a 4- to 6-membered ring, or at least one hydrogen atom is bonded to R 1-1 wherein each R 1-1 are independently amino, hydroxy, hydroxy-substituted C 1-6 alkyl, 5- or 6-membered monocyclic heteroaryl; Ring A is TIFF2025530470000003.tif23170where, X 1is CH or N, and X 2 is CH or N; Ring B is a 5- to 10-membered heteroaryl, at least one hydrogen atom TIFF2025530470000004.tif121705-10 membered heteroaryl, 5-10 membered heteroaryl ketone group, at least one hydrogen TIFF2025530470000005.tif121705-10-membered heteroaryl ketone group, wherein L is absent, -CH2-, -NH-, -O-, -S-, -SO-, or -SO2-; Each R 3 are independently hydroxyl, TIFF2025530470000006.tif9170C 1-6 Alkyl, at least one hydrogen is R 3-1 C replaced with 1-6 Alkyl, amino, at least one hydrogen is R 3-1 Amino substituted with 3- to 6-membered heterocycloalkyl, at least one hydrogen atom is R 3-1 3-6 membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is substituted by R 3-1 is a 5- or 6-membered monocyclic heteroaryl substituted with Each R 3-1 are independently hydroxy, C with at least one hydrogen replaced by hydroxy 1-4 Alkyl, C 1-4 Alkoxy, halogen; Ring C is phenyl, and at least one hydrogen is R 4 phenyl substituted with 3- to 7-membered monocycloalkyl, at least one hydrogen atom is R 4 3-7 membered monocycloalkyl substituted with C 5-12 Bridged bicycloalkyl, at least one hydrogen is R 4 C replaced with 5-12 Bridged bicycloalkyl, C 10-20 Bridged tricycloalkyl, at least one hydrogen is R 4 C replaced with 10-20Bridged tricycloalkyl, 8- to 10-membered benzocycloalkyl, at least one hydrogen atom is R 4 is an 8- to 10-membered benzocycloalkyl substituted with Each R 4 is independently C 1-4 Alkyl, C with at least one hydrogen replaced by halogen 1-4 Alkyl, halogen, 3-6 membered cycloalkyl, C 1-4 Alkoxy, C with at least one hydrogen replaced by halogen 1-4 Alkoxy, C 1-4 Alkylthiols, C with at least one hydrogen replaced by a halogen 1-4 Alkylthiols and halogen-substituted mercaptans.

[0012] In some preferred embodiments, the structure represented by general formula (I) is general formula (I'). TIFF2025530470000007.tif47170

[0013] where X 1 is CH or N, and X 2 is CH or N.

[0014] In some preferred embodiments, X 1 and X 2 is not N at the same time.

[0015] In some preferred embodiments, each R 1 are independently methyl, ethyl, or at least one hydrogen atom in R 1-1 methyl substituted with at least one hydrogen atom; 1-1 ethyl, vinyl, 1-propenyl, or 2-propenyl substituted with

[0016] In some preferred embodiments, each R 2 are independently methyl, ethyl, or at least one hydrogen atom in R 1-1 methyl substituted with at least one hydrogen atom; 1-1 ethyl, vinyl, 1-propenyl, or 2-propenyl substituted with

[0017] In some preferred embodiments, R 1-1 is amino, hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl; In some preferred embodiments, R 1 and R 2 are bonded to each other to form a 4- to 6-membered ring, or R 1 and R 2 are bonded together so that at least one hydrogen is R 1-1 Forms a 4- to 6-membered ring substituted with

[0018] In some preferred embodiments, R 1 and R 2 are bonded to each other to form a 4- to 6-membered ring, or R 1 and R 2 are bonded together so that at least one hydrogen is R 1-1 and the 4- to 6-membered ring contains zero, one, two, or three other heteroatoms selected from N, O, and S (excluding the P atom to which R1 and R2 are commonly bonded).

[0019] In some preferred embodiments, each R 1-1 is independently amino, hydroxy, methyl substituted with hydroxy, ethyl substituted with hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl.

[0020] In some preferred embodiments, ring A is The file is TIFF2025530470000008.tif23170.

[0021] In some preferred embodiments, Ring B is a 5-membered nitrogen-containing monocyclic heteroaryl, a 6-membered nitrogen-containing monocyclic heteroaryl, or a ring in which at least one hydrogen atom is TIFF2025530470000009.tif11170, a five-membered nitrogen-containing monocyclic heteroaryl substituted with at least one hydrogen atom 6-membered nitrogen-containing monocyclic heteroaryl, 8-10-membered nitrogen-containing fused-ring heteroaryl, at least one hydrogen atom of which is substituted with TIFF2025530470000010.tif11170 8-10 membered nitrogen-containing fused ring heteroaryl substituted with TIFF2025530470000011.tif11170, 5 membered nitrogen-containing monocyclic heteroaryl ketone group, 6 membered nitrogen-containing monocyclic heteroaryl ketone group, at least one hydrogen atom of which is TIFF2025530470000012.tif11170 substituted five-membered nitrogen-containing monocyclic heteroaryl ketone group, at least one hydrogen TIFF2025530470000013.tif11170 is a 6-membered nitrogen-containing monocyclic heteroaryl ketone group substituted with

[0022] In some preferred embodiments, ring C is phenyl, at least one hydrogen is R 4 phenyl substituted with 4- to 6-membered monocycloalkyl, at least one hydrogen atom is R 4 4-6 membered monocycloalkyl substituted with C 5-8 Bridged bicycloalkyl, at least one hydrogen is R 4 C replaced with 5-12 Bridged bicycloalkyl, C 10-20 Bridged tricycloalkyl, at least one hydrogen is R 4 C replaced with 10-20 Bridged tricycloalkyl, 8- to 10-membered benzocycloalkyl, at least one hydrogen atom is R 4 is an 8- to 10-membered benzocycloalkyl substituted with

[0023] In some preferred embodiments, in ring B, the 5- or 6-membered nitrogen-containing monocyclic heteroaryl is The file is TIFF2025530470000014.tif109170.

[0024] In some preferred embodiments, in the ring B, the at least one hydrogen atom is TIFF2025530470000015.tif11170 is a substituted five-membered nitrogen-containing monocyclic heteroaryl The file is TIFF2025530470000016.tif59170.

[0025] In some preferred embodiments, in the ring B, the at least one hydrogen atom is TIFF2025530470000017.tif11170 is a substituted 6-membered nitrogen-containing monocyclic heteroaryl The file is TIFF2025530470000018.tif22170.

[0026] In some preferred embodiments, in the ring B, the 8-10 membered nitrogen-containing monocyclic heteroaryl is The file is TIFF2025530470000019.tif21170.

[0027] In some preferred embodiments, in the ring B, the at least one hydrogen atom is TIFF2025530470000020.tif11170 substituted 8-10 membered nitrogen-containing monocyclic heteroaryl The file is TIFF2025530470000021.tif21170.

[0028] In some preferred embodiments, in ring B, the 6-membered nitrogen-containing monocyclic heteroaryl ketone group is a pyridone group.

[0029] In some preferred embodiments, the six-membered nitrogen-containing monocyclic heteroaryl ketone group is In some preferred embodiments, the at least one hydrogen atom is TIFF2025530470000023.tif11170-substituted six-membered nitrogen-containing monocyclic heteroaryl ketone groups have at least one hydrogen atom TIFF2025530470000024.tif11170 is a substituted pyridone group.

[0030] In some preferred embodiments, the at least one hydrogen TIFF2025530470000025.tif11170 is a substituted six-membered nitrogen-containing monocyclic heteroaryl ketone group In some preferred embodiments, in the ring C, the at least one hydrogen atom is R 4 Phenyl substituted with The file is TIFF2025530470000027.tif21170.

[0031] In some preferred embodiments, in the ring C, the 4- to 6-membered monocycloalkyl is a cycloalkyl, cyclopentyl, or cyclobutyl.

[0032] In some preferred embodiments, in the ring C, the one hydrogen atom is R 4 4-6 membered monocycloalkyl substituted with The file is TIFF2025530470000028.tif15170.

[0033] In some preferred embodiments, in the ring C, 5-8 Bridged bicycloalkyls include bicyclo[1.1.1]pentyl and bicyclo[2.2.2]octyl.

[0034] In some preferred embodiments, in the ring C, the at least one hydrogen atom is R 4 C replaced with 5-12 Bridged bicycloalkyl has one hydrogen atom in R 4 bicyclo[1.1.1]pentyl substituted with or one hydrogen is R 4 and bicyclo[2.2.2]octyl substituted with .

[0035] In some preferred embodiments, in the ring C, 10-20 The bridged tricycloalkyl is adamantyl.

[0036] In some preferred embodiments, in the ring C, the at least one hydrogen atom is R 4 C replaced with 10-20 Bridged tricycloalkyl has one hydrogen atom in R 4 and adamantyl substituted with .

[0037] In some preferred embodiments, in ring C, the 8- to 10-membered benzocycloalkyl is benzocyclopentyl, benzocyclobutyl, or benzocyclohexyl.

[0038] In some preferred embodiments, in the ring C, the at least one hydrogen atom is R 4 8-10 membered benzocycloalkyl substituted with at least one hydrogen atom is R 4 benzocyclopentyl substituted with at least one hydrogen atom of R 4 or a benzocyclobutyl substituted with at least one hydrogen atom in which R 4 and benzocyclohexyl substituted with .

[0039] In some preferred embodiments, each R 3 are independently hydroxyl, cyano, C 1-4 Alkyl, at least one hydrogen is R 3-1 C replaced with 1-4 Alkyl, amino, at least one hydrogen is R 3-1 Amino substituted with 3- to 6-membered azacycloalkyl, 3- to 6-membered oxacycloalkyl, at least one hydrogen atom of which is R 3-1 3-6 membered azacycloalkyl substituted with at least one hydrogen atom of R 3-1 3-6 membered oxacycloalkyl substituted with 6 membered nitrogen-containing monocyclic heteroaryl, at least one hydrogen atom of which is R 3-1 is a 6-membered nitrogen-containing monocyclic heteroaryl substituted with

[0040] In some preferred embodiments, each R 3are independently hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and at least one hydrogen atom is present in R 3-1 methyl substituted with at least one hydrogen atom; 3-1 ethyl substituted with at least one hydrogen atom; 3-1 n-propyl substituted with at least one hydrogen atom 3-1 isopropyl, amino, at least one hydrogen is substituted with R 3-1 amino substituted with The file is TIFF2025530470000029.tif96170.

[0041] In some preferred embodiments, each R 3-1 are independently hydroxy, methyl having at least one hydrogen substituted with hydroxy, ethyl having at least one hydrogen substituted with hydroxy, n-propyl having at least one hydrogen substituted with hydroxy, isopropyl having at least one hydrogen substituted with hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, or iodine; In some preferred embodiments, each R 4 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methyl in which at least one hydrogen is substituted with fluorine, ethyl in which at least one hydrogen is substituted with fluorine, n-propyl in which at least one hydrogen is substituted with fluorine, isopropyl in which at least one hydrogen is substituted with fluorine, fluorine, chlorine, bromine, iodine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, hexafluoroethoxy, methyl mercapto, ethyl mercapto, n-propyl mercapto, isopropyl mercapto, methyl mercapto in which at least one hydrogen is substituted with fluorine or ethyl mercapto in which at least one hydrogen is substituted with fluorine, or a halogen-substituted mercaptan (preferably a fluorine-substituted mercaptan, more preferably pentafluoromercaptan).

[0042] In some preferred embodiments, the compound is selected from any one of the following compounds: TIFF2025530470000030.tif240170TIFF2025530470000031.tif221170TIFF2025530470000032.tif252170TIFF2025530470 000033.tif227170TIFF2025530470000034.tif215170TIFF2025530470000035.tif221170TIFF2025530470000036.tif25217 0TIFF2025530470000037.tif246170TIFF2025530470000038.tif240170TIFF2025530470000039.tif215170TIFF2025530470 000040.tif233170TIFF2025530470000041.tif215170TIFF2025530470000042.tif215170TIFF2025530470000043.tif52170

[0043] A second aspect of the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0044] A third aspect of the present invention provides the use of a compound according to the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention, in the manufacture of a medicament or pharmaceutical composition for use in one or more applications selected from the following: (i) binds to TEAD; preferably binds to the palmitoyl pocket of TEAD; (ii) inhibition of TEAD transcript levels; (iii) inhibition / blocking of YAP-TEAD binding; (iv) regulation of the Hippo signaling pathway; and (v) Treatment of diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway.

[0045] A fourth aspect of the present invention provides the use of a compound according to the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention, for use in: (i) binds to TEAD; preferably binds to the palmitoyl pocket of TEAD; (ii) inhibition of TEAD transcript levels; (iii) inhibition / blocking of YAP-TEAD binding; (iv) regulation of the Hippo signaling pathway; and (v) treating diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway; and / or (vi) The manufacture of a pharmaceutical for treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or impairment of the Hippo signaling pathway.

[0046] A fifth aspect of the present invention provides a method for treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or a disorder of the Hippo signaling pathway, the method comprising the steps of: administering to a subject a compound according to the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; or Administering the pharmaceutical composition according to the second aspect of the invention to a subject.

[0047] Compared with the prior art, the present invention has at least the following advantages:

[0048] (1) The compounds provided in the first aspect of the present invention and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, or the pharmaceutical compositions provided in the second aspect of the present invention, effectively inhibit / block YAP-TEAD binding and inhibit / block YAP-TEAD transcriptional function by targeting the palmitoyl pocket of TEAD, thereby enabling the prevention and / or treatment of diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway.

[0049] (2) The compound provided in the first aspect of the present invention and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition provided in the second aspect of the present invention has a strong affinity for TEAD proteins.

[0050] (3) The compound provided in the first aspect of the present invention and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition provided in the second aspect of the present invention has excellent metabolic stability and pharmacokinetic properties.

[0051] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described one by one here due to space limitations. [Brief explanation of the drawings]

[0052] One or more embodiments are illustratively illustrated by the figures in the accompanying drawings, and these illustrative illustrations do not constitute limitations on the embodiments.

[0053] One or more embodiments are illustratively illustrated by the figures in the accompanying drawings, and these illustrative illustrations do not constitute limitations on the embodiments. [Figure 1]FIG. 1 shows a mass spectrum after incubating compound 68 with TEAD1 protein in an example of the present invention. [Figure 2] FIG. 2 is a mass spectrum after incubating compound 68 with TEAD4 protein in an example of the present invention. [Figure 3a] FIG. 3a is a graph showing the results of an in vitro liver microsome stability test of compound 8 in an example of the present invention, in which the half-life in mice is 75.4 minutes, the half-life in humans is 118 minutes, the half-life in rats is 157 minutes, and the half-life in dogs is 177 minutes. [Figure 3b] FIG. 3b is a graph showing the results of an in vitro liver microsome stability test of Compound 1 in an example of the present invention, where the mouse half-life is 93.8 minutes and the human half-life is 359 minutes. [Figure 3c] FIG. 3c is a graph showing the results of an in vitro liver microsome stability test of compound 9 in an example of the present invention, where the half-life in mice is 85.6 minutes and the half-life in humans is 29.3 minutes. [Figure 3d] FIG. 3d is a graph showing the results of an in vitro liver microsome stability test of compound 10 in an example of the present invention, where the half-life in mice is 105 minutes and the half-life in humans is 50.8 minutes. [Figure 3e] FIG. 3e is a graph showing the results of an in vitro liver microsome stability test of compound 17 in an example of the present invention, in which the half-life in mice is 33.9 minutes, the half-life in rats is 48.0 minutes, the half-life in dogs is 141 minutes, and the half-life in humans is 107 minutes. [Figure 3f] Figure 3f is a graph showing the results of an in vitro liver microsome stability study of compound 64 in an example of the present invention, where the left graph is for mice, with a mouse half-life of >186 minutes, and the right graph is for humans, with a human half-life of >186 minutes. [Figure 3g]Figure 3g is a graph showing the results of an in vitro liver microsome stability test of compound 28 in an example of the present invention, where the left graph is for mice, with a mouse half-life of >186 minutes, and the right graph is for humans, with a human half-life of >186 minutes. [Figure 3h] Figure 3h is a graph showing the results of an in vitro liver microsome stability test of compound 68 in an example of the present invention, where the left graph is for mice, with a mouse half-life of >186 minutes, and the right graph is for humans, with a human half-life of >186 minutes. [Figure 4a] FIG. 4a is a graph showing the average blood drug concentration of Compound 17 in an example of the present invention after oral administration (10.0 mg / kg) and injection administration (1.0 mg / kg) to mice. [Figure 4b] FIG. 4b is a graph showing the average blood drug concentration of Compound 64, an example of the present invention, after oral administration (10.0 mg / kg) and injection administration (1.0 mg / kg) to mice. [Figure 4c] FIG. 4c is a semi-logarithmic graph of the mean blood drug concentration after oral administration (10.0 mg / kg) and injection administration (1.0 mg / kg) of Compound 64, an example of the present invention, to mice. [Figure 5] FIG. 5 is a schematic diagram of a competitive sulfhydryl group binding experiment of compounds in examples of the present invention. [Figure 6a] FIG. 6a is a graph showing the average blood concentration of Compound 17 in SD rats in an example of the present invention. [Figure 6b] FIG. 6b is a semi-logarithmic graph of the mean blood concentration of Compound 17 in SD rats in an example of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0054] The present invention provides a group of small molecule compounds having a phosphorylated aryl structure, preferably a small molecule compound having a polysubstituted phosphorylated aryl structure, which can bind to the palmitoyl pocket of TEAD, thereby inhibiting / blocking YAP-TEAD binding, inhibiting / blocking YAP-TEAD transcriptional function, and blocking the transcriptional activity of the Hippo signaling pathway. It is expected that this compound will treat diseases caused by disorders of the Hippo signaling pathway and overactivation of YAP1, and will reverse the problems of drug resistance and recurrence that occur with existing therapeutic agents for these diseases.

[0055] compound In one aspect, embodiments of the present invention provide compounds having the structure shown in general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: TIFF2025530470000044.tif42170

[0056] where: Z is -CH2-, -NH(CH2)n-, -O(CH2)n-, -S-, -SO-, or -SO2-, where each n is independently an integer of 0 to 3; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, at least one hydrogen is R 1-1 C replaced with 1-6 Alkyl, at least one hydrogen is R 1-1 C replaced with 2-6 is alkenyl; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, at least one hydrogen is R 1-1 C replaced with 1-6 Alkyl, at least one hydrogen is R 1-1 C replaced with 2-6 is alkenyl; Or, R 1 and R 2 are bonded to form a 4- to 6-membered ring, or at least one hydrogen atom is bonded to R 1-1 wherein each R 1-1are independently amino, hydroxy, hydroxy-substituted C 1-6 alkyl, 5- or 6-membered monocyclic heteroaryl; Ring A is TIFF2025530470000045.tif23170where, X 1 is CH or N, and X 2 is CH or N; Ring B is a 5- to 10-membered heteroaryl, at least one hydrogen atom TIFF2025530470000046.tif11170 substituted 5-10 membered heteroaryl; wherein L is absent, -CH2-, -NH-, -O-, -S-, -SO-, or -SO2-; Each R 3 are independently hydroxyl, TIFF2025530470000047.tif9170C 1-6 Alkyl, at least one hydrogen is R 3-1 C replaced with 1-6 Alkyl, amino, at least one hydrogen is R 3-1 Amino substituted with 3- to 6-membered heterocycloalkyl, at least one hydrogen atom is R 3-1 3-6 membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is substituted by R 3-1 is a 5- or 6-membered monocyclic heteroaryl substituted with Each R 3-1 are independently hydroxy, C with at least one hydrogen replaced by hydroxy 1-4 Alkyl, C 1-4 Alkoxy, halogen; Ring C is phenyl, and at least one hydrogen is R 4 phenyl substituted with 3- to 7-membered monocycloalkyl, at least one hydrogen atom is R 4 3-7 membered monocycloalkyl substituted with C 5-12 Bridged bicycloalkyl, at least one hydrogen is R 4 C replaced with 5-12 Bridged bicycloalkyl, C 10-20 Bridged tricycloalkyl, at least one hydrogen is R4 C replaced with 10-20 Bridged tricycloalkyl, 8- to 10-membered benzocycloalkyl, at least one hydrogen atom is R 4 is an 8- to 10-membered benzocycloalkyl substituted with Each R 4 is independently C 1-4 Alkyl, C with at least one hydrogen replaced by halogen 1-4 Alkyl, halogen, 3-6 membered cycloalkyl, C 1-4 Alkoxy, C with at least one hydrogen replaced by halogen 1-4 Alkoxy, C 1-4 Alkylthiols, C with at least one hydrogen replaced by a halogen 1-4 It is an alkylthiol, a mercaptan, or a halogen-substituted mercaptan.

[0057] R 1 and R 2 In a preferred embodiment of the present invention, R 1 is C 1-4 alkyl, more preferably methyl or ethyl, for example methyl; R 2 is C 1-4 It is alkyl, more preferably methyl or ethyl, for example methyl.

[0058] In a preferred embodiment of the present invention, R 1 is C 2-4 alkenyl, more preferably vinyl, 1-propenyl, 2-propenyl, for example vinyl; R 2 is C 2-4 It is preferably alkenyl, more preferably vinyl, 1-propenyl, or 2-propenyl, for example vinyl.

[0059] In some other preferred embodiments of the present invention, R 1 and R 2 are bonded to form a 4- to 6-membered ring, or at least one hydrogen atom is bonded to R 1-1 wherein each R 1-1are independently amino, hydroxy, hydroxy-substituted C 1-6 alkyl, 5- or 6-membered monocyclic heteroaryl.

[0060] In some other preferred embodiments of the present invention, each R 1-1 is independently amino, hydroxy, methyl substituted with hydroxy, ethyl substituted with hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl (eg, pyridinyl).

[0061] In a preferred embodiment of the present invention, R 1 has one hydrogen atom R 1-1 C replaced with 1-4 alkyl, where R 1-1 is amino, hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl. More preferably, R 1 has one hydrogen atom R 1-1 Methyl substituted with or one hydrogen atom is R 1-1 ethyl substituted with, where R 1-1 is amino, hydroxy, or a 6-membered nitrogen-containing monocyclic heteroaryl. More preferably, R 1 has one hydrogen atom R 1-1 Methyl substituted with or one hydrogen atom is R 1-1 where each R 1-1 is independently amino, hydroxy or pyridinyl. For example, The file is TIFF2025530470000048.tif9170.

[0062] In a preferred embodiment of the present invention, R 2 has one hydrogen atom R 1-1 C replaced with 1-4 alkyl, where R 1-1 is amino, hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl. More preferably, R 2 has one hydrogen atom R 1-1 Methyl substituted with or one hydrogen atom is R 1-1 ethyl substituted with, where R1-1 is amino, hydroxy, or a 6-membered nitrogen-containing monocyclic heteroaryl. More preferably, R 1 has one hydrogen atom R 1-1 Methyl substituted with or one hydrogen atom is R 1-1 where each R 1-1 is independently amino, hydroxy or pyridinyl. For example, The file is TIFF2025530470000049.tif9170.

[0063] In a preferred embodiment of the present invention, R 1 and R 2 are bonded to each other to form a 4- to 6-membered ring. More preferably, R 1 is ethyl, TIFF2025530470000050.tif8170R 1 and R 2 are combined with each other Form TIFF2025530470000051.tif15170.

[0064] In a preferred embodiment of the present invention, R 1 and R 2 are bonded to each other to form a 4- to 6-membered ring in which at least one hydrogen atom is replaced with a hydroxyl. For example, TIFF2025530470000052.tif9170R 2 is methyl, R 1 The β-carbon and R 2 are combined with each other Form TIFF2025530470000053.tif11170.

[0065] Z In a preferred embodiment of the present invention, Z is —CH 2 —, —NH(CH 2 ) n —, —O(CH 2 ) n —, —S—, —SO—, or —SO 2 —, and each n is independently an integer of 0 to 3.

[0066] In a preferred embodiment of the present invention, n is 1.

[0067] In a preferred embodiment of the present invention, Z is —CH 2 —, —NH(CH 2 )—, —O(CH 2 )—, —S—, —SO—, —SO 2 —.

[0068] In a preferred embodiment of the present invention, when Z contains a heteroatom (N, O or S), the heteroatom in Z is connected to ring A via a covalent bond. For example, when Z is -NH(CH)-, the N atom is connected to ring A via a covalent bond. Connected to TIFF2025530470000054.tif22170, For example, if Z is -O(CH2)-, the O atom is bonded to the Connected to TIFF2025530470000056.tif22170, Form TIFF2025530470000057.tif26170.

[0069] Ring A In a preferred embodiment of the present invention, ring A is The file is TIFF2025530470000058.tif23170.

[0070] Ring B In a preferred embodiment of the present invention, ring B is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl, said 5- or 6-membered nitrogen-containing monocyclic heteroaryl being TIFF2025530470000059.tif109170. More preferably, the 5- or 6-membered nitrogen-containing monocyclic heteroaryl is TIFF2025530470000060.tif34170.

[0071] In a preferred embodiment of the present invention, ring B has at least one hydrogen atom. TIFF2025530470000061.tif11170 is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl substituted with

[0072] In a preferred embodiment of the present invention, ring B has at least one hydrogen atom. TIFF2025530470000062.tif11170, wherein said at least one hydrogen is The five-membered nitrogen-containing monocyclic heteroaryl substituted with TIFF2025530470000063.tif11170 is preferably TIFF2025530470000064.tif60170 wherein each L is independently absent, -CH2-, -NH-, -O-, -S-, -SO-, or -SO2-. When L is absent, the at least one hydrogen atom is The five-membered nitrogen-containing monocyclic heteroaryl substituted with TIFF2025530470000065.tif11170 is preferably TIFF2025530470000066.tif64170.

[0073] In a preferred embodiment of the present invention, ring B has at least one hydrogen atom. TIFF2025530470000067.tif11170, wherein said at least one hydrogen is The 6-membered nitrogen-containing monocyclic heteroaryl substituted with TIFF2025530470000068.tif11170 is preferably TIFF2025530470000069.tif22170 wherein each L is independently absent, -CH2-, -NH-, -O-, -S-, -SO-, or -SO2-. When L is absent, the at least one hydrogen atom is The 6-membered nitrogen-containing monocyclic heteroaryl substituted with TIFF2025530470000070.tif11170 is preferably TIFF2025530470000071.tif21170. In a preferred example, the at least one hydrogen TIFF2025530470000072.tif11170 substituted 6-membered nitrogen-containing monocyclic heteroaryl TIFF2025530470000073.tif22170 where, TIFF2025530470000074.tif12170 Ring B The file is TIFF2025530470000075.tif23170.

[0074] In a preferred embodiment of the present invention, ring B is an 8- to 10-membered nitrogen-containing fused ring heteroaryl, and said 8- to 10-membered nitrogen-containing fused ring heteroaryl is preferably TIFF2025530470000076.tif21170. More preferably, the 8- to 10-membered nitrogen-containing fused ring heteroaryl is preferably a 9-membered nitrogen-containing fused ring heteroaryl, for example The file is TIFF2025530470000077.tif18170.

[0075] In a preferred embodiment of the present invention, ring B has at least one hydrogen atom. TIFF2025530470000078.tif11170, wherein each L is independently absent, -CH2-, -NH-, -O-, -S-, -SO-, or -SO2-. More preferably, the at least one hydrogen is TIFF2025530470000079.tif11170 substituted 8-10 membered nitrogen-containing fused ring heteroaryl TIFF2025530470000080.tif21170. When L is absent, the at least one hydrogen is The 8-10 membered nitrogen-containing fused ring heteroaryl substituted with TIFF2025530470000081.tif11170 is preferably The file is TIFF2025530470000082.tif18170.

[0076] In a preferred embodiment of the present invention, ring B is a 5- to 10-membered heteroaryl ketone group. More preferably, ring B is a 5- or 6-membered heteroaryl ketone group. More preferably, ring B is a 6-membered heteroaryl ketone group. More preferably, ring B is pyridone. More preferably, ring B is TIFF2025530470000083.tif21170

[0077] In a preferred embodiment of the present invention, ring B has at least one hydrogen atom. TIFF2025530470000084.tif11170. More preferably, ring B is a 5- to 10-membered heteroaryl ketone group substituted with at least one hydrogen atom. More preferably, ring B is a 5- or 6-membered heteroaryl ketone group substituted with at least one hydrogen atom. More preferably, ring B is a 6-membered heteroaryl ketone group substituted with at least one hydrogen atom. TIFF2025530470000087.tif11170. More preferably, ring B is TIFF2025530470000088.tif21170 for example The file is TIFF2025530470000089.tif20170.

[0078] R 3 In the present invention, R 3 is bonded to L TIFF2025530470000090.tif11170 and further connected to ring B, wherein each L is independently absent, -CH-, -NH-, -O-, -CHO-, -S-, -SO-, or -SO-. It should be understood that the various groups formed by the combination of each L with R are all within the scope of the present invention.

[0079] In a preferred embodiment of the present invention, R 3is C 1-6 alkyl, more preferably C 1-4 It is alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl.

[0080] In a preferred embodiment of the present invention, in order to obtain a compound with high affinity for TEAD proteins, R 3 is a 3- to 6-membered heterocycloalkyl, more preferably a 3- to 6-membered azacycloalkyl or a 3- to 6-membered oxacycloalkyl. More preferably, the 3- to 6-membered azacycloalkyl is preferably TIFF2025530470000091.tif15170 for example TIFF2025530470000092.tif10170. More preferably, the 3- to 6-membered oxacycloalkyl is preferably TIFF2025530470000093.tif28170. More preferably, the 3- to 6-membered oxacycloalkyl is oxetanyl or oxepentanyl, for example TIFF2025530470000094.tif12170. Also, compared to nitrogen heterocycloalkyl, R 3 Compounds in which is a 3- to 6-membered oxacycloalkyl have stronger affinity for TEAD proteins.

[0081] In a more preferred embodiment, R 3 When the L linker attached to R contains oxygen and sulfur, for example, R 3 When the L atom bonded to R is -O-, -CHO-, -S-, -SO-, or -SO-, the compound has a stronger affinity for the TEAD protein. 3 When the L linker attached to is -O- or -CHO-, the compound has stronger affinity for the TEAD protein.

[0082] In a more preferred embodiment, R 3When the L atom bonded to R is -O- or -S-, the compound has a stronger affinity for TEAD proteins. 3 The L atom bonded to is -O-, TIFF2025530470000095.tif12170The compound has a stronger affinity for TEAD proteins.

[0083] In a more preferred embodiment, R 3 The L atom bonded to is O and R 3 When is a 3- to 6-membered oxacycloalkyl, the compound has a stronger affinity for TEAD proteins.

[0084] In a preferred embodiment of the present invention, R 3 is a 5- or 6-membered monocyclic heteroaryl, and said 5- or 6-membered nitrogen-containing monocyclic heteroaryl is TIFF2025530470000096.tif109170. More preferably, R 3 is a 6-membered nitrogen-containing monocyclic heteroaryl, more preferably R 3 teeth TIFF2025530470000097.tif53170. For example, R 3 teeth The file is TIFF2025530470000098.tif14170.

[0085] In a preferred embodiment of the present invention, R 3 is amino or at least one hydrogen is R 3-1 and amino substituted with, for example The file is TIFF2025530470000099.tif9170.

[0086] In a preferred embodiment of the present invention, R 3 is hydroxy.

[0087] In a preferred embodiment of the present invention, R 3 teeth The file is TIFF2025530470000100.tif8170.

[0088] In a preferred embodiment of the present invention, R 3 has at least one hydrogen atom in R 3-1 C replaced with 1-6 More preferably, R 3 has at least one hydrogen atom in R 3-1 C replaced with 1-4 More preferably, R 3 has at least one hydrogen atom in R 3-1 methyl substituted with at least one hydrogen atom; 3-1 ethyl substituted with at least one hydrogen atom; 3-1 or n-propyl substituted with at least one hydrogen atom in R 3-1 More preferably, R 3 is methyl in which at least one hydrogen is replaced by methoxy, ethyl in which at least one hydrogen is replaced by methoxy, methyl in which at least one hydrogen is replaced by hydroxy, or methyl in which at least one hydrogen is replaced by fluorine. For example, TIFF2025530470000101.tif9170Difluoromethyl or trifluoromethyl.

[0089] In a preferred embodiment of the present invention, R 3 has at least one hydrogen atom in R 3-1 More preferably, R 3 has at least one hydrogen atom in R 3-1 More preferably, R 3 has at least one hydrogen atom in R 3-1 More preferably, R is a 5- or 6-membered heterocycloalkyl substituted with 3 has at least one hydrogen atom in R 3-1 or a 5-membered azetidinyl substituted with at least one hydrogen atom in R 3-1 More preferably, R 3 teeth TIFF2025530470000102.tif16170. More preferably, R 3 is a 5-membered ring azetidinyl in which at least one hydrogen is replaced by hydroxy or methyl, or a 5-membered ring oxiranyl in which at least one hydrogen is replaced by hydroxy or methyl, for example The file is TIFF2025530470000103.tif16170.

[0090] In a preferred embodiment of the present invention, R 3 has at least one hydrogen atom in R 3-1 More preferably, R is a 5- or 6-membered monocyclic heteroaryl substituted with 3 has at least one hydrogen atom in R 3-1 More preferably, R is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl substituted with 3 has at least one hydrogen atom in R 3-1 More preferably, R is a 6-membered nitrogen-containing monocyclic heteroaryl substituted with 3 has at least one hydrogen atom in R 3-1 pyridinyl substituted with; for example The file is TIFF2025530470000104.tif21170.

[0091] R 3-1 In a preferred embodiment of the present invention, R 3-1 is hydroxy.

[0092] In a preferred embodiment of the present invention, R 3-1 is a halogen, more preferably fluorine, chlorine, bromine or iodine; for example, fluorine.

[0093] In a preferred embodiment of the present invention, R 3-1 is a C in which at least one hydrogen is replaced by hydroxy. 1-4 More preferably, R 3-1 is methyl in which one hydrogen is replaced by hydroxy or ethyl in which one hydrogen is replaced by hydroxy, for example The file is TIFF2025530470000105.tif14170.

[0094] In a preferred embodiment of the present invention, R 3-1 is C 1-4 Alkoxy is more preferred. It is methoxy, ethoxy or propoxy. For example, methoxy.

[0095] Ring C In a preferred embodiment of the present invention, ring C is phenyl or at least one hydrogen is R 4 More preferably, said at least one hydrogen is substituted with R 4 Phenyl substituted with TIFF2025530470000106.tif21170 for example The file is TIFF2025530470000107.tif41170.

[0096] In order to obtain a compound having a higher affinity for TEAD protein, in a preferred embodiment of the present invention, Z is —NH(CH)—, —O(CH), and ring C is phenyl or at least one hydrogen atom is R 4 More preferably, Z-ring C is phenyl substituted with TIFF2025530470000108.tif21170. For example: The file is TIFF2025530470000109.tif21170.

[0097] Ring C is phenyl or at least one hydrogen is R 4 When the phenyl is substituted with , the compounds of the present invention have relatively high metabolic kinetic properties.

[0098] In a preferred embodiment of the present invention, ring C is a 3- to 7-membered monocycloalkyl. More preferably, ring C is a 4- to 6-membered monocycloalkyl. More preferably, ring C is a cycloalkyl group, cyclopentyl, or cyclobutyl, for example, cyclohexyl.

[0099] In a preferred embodiment of the present invention, ring C has at least one hydrogen atom selected from R 4 More preferably, the at least one hydrogen is substituted with R 4 More preferably, the at least one hydrogen is substituted with R 4 4-6 membered monocycloalkyl substituted with TIFF2025530470000110.tif15170 for example The file is TIFF2025530470000111.tif16170.

[0100] In a preferred embodiment of the present invention, in order to obtain a compound having a higher affinity for TEAD protein, Z is —NH(CH)—, —O(CH), and ring C is a 3- to 7-membered monocycloalkyl or a 3- to 7-membered monocycloalkyl group in which at least one hydrogen atom is replaced by R. 4 More preferably, ring C is a 4- to 6-membered monocycloalkyl or a 3- to 7-membered monocycloalkyl substituted with one hydrogen atom. 4 For example, Z-ring C is The file is TIFF2025530470000112.tif17170.

[0101] In a preferred embodiment of the present invention, ring C is C 5-12 Bridged bicycloalkyl or at least one hydrogen atom is R 4 C replaced with 5-12 More preferably, ring C is C 5-8 Bridged bicycloalkyl or one hydrogen atom is R 4 C replaced with 5-12 More preferably, ring C is bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, or a bridged bicycloalkyl group where one hydrogen is R 4 bicyclo[1.1.1]pentyl substituted with or one hydrogen is R 4 Bicyclo[2.2.2]octyl substituted with, for example: The file is TIFF2025530470000113.tif17170.

[0102] In a preferred embodiment of the present invention, ring C is C 10-20 Bridged tricycloalkyl At least one hydrogen is R 4 C replaced with 10-20 More preferably, ring C is adamantyl or a ring in which one hydrogen is R 4 Adamantyl substituted with, for example: The file is TIFF2025530470000114.tif17170.

[0103] In a preferred embodiment of the present invention, ring C is an 8- to 10-membered benzocycloalkyl. More preferably, ring C is benzocyclopentyl, benzocyclobutyl, or benzocyclohexyl. For example, ring C is The file is TIFF2025530470000115.tif15170.

[0104] In a preferred embodiment of the present invention, ring C has at least one hydrogen atom selected from R 4 More preferably, at least one hydrogen is substituted with R 4 benzocyclopentyl substituted with at least one hydrogen atom of R 4 or a benzocyclobutyl substituted with at least one hydrogen atom in which R 4 More preferably, the at least one hydrogen is substituted with R 4 8-10 membered benzocycloalkyl substituted with TIFF2025530470000116.tif15170. For example, ring C is The file is TIFF2025530470000117.tif15170.

[0105] R 4 In a preferred embodiment of the present invention, R 4 is C 1-4Alkyl or C in which at least one hydrogen is replaced by halogen 1-4 More preferably, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methyl in which at least one hydrogen is replaced with a halogen, ethyl in which at least one hydrogen is replaced with a halogen, n-propyl in which at least one hydrogen is replaced with a halogen, or isopropyl in which at least one hydrogen is replaced with a halogen. More preferably, R 4 is trifluoromethyl or hexafluoroethyl, for example trifluoromethyl.

[0106] In a preferred embodiment of the present invention, R 4 is halogen. More preferably, R 4 is fluorine, chlorine, bromine or iodine, for example bromine or fluorine.

[0107] In a preferred embodiment of the present invention, R 4 is a 3- to 6-membered cycloalkyl. More preferably, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, for example: cyclopropyl.

[0108] In a preferred embodiment of the present invention, R 4 is C 1-4 Alkoxy or C in which at least one hydrogen is replaced by halogen 1-4 More preferably, R 4 is methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, hexafluoroethoxy. More preferably, R 4 is trifluoromethoxy or hexafluoroethoxy, for example trifluoromethoxy.

[0109] In a preferred embodiment of the present invention, R 4 is C 1-4 Alkylthiol or C in which at least one hydrogen is replaced by halogen 1-4More preferably, R 4 is methyl mercapto, ethyl mercapto, n-propyl mercapto, isopropyl mercapto, methyl mercapto in which at least one hydrogen is substituted with fluorine, or ethyl mercapto in which at least one hydrogen is substituted with fluorine. More preferably, R 4 is trifluoromethylmercapto or hexafluoroethylmercapto, for example trifluoromethylmercapto.

[0110] In a preferred embodiment of the present invention, R 4 is a mercapto or halogen-substituted mercaptan, preferably a fluorine-substituted mercaptan, such as pentafluoromercaptan.

[0111] Based on the beneficial effect of exhibiting excellent binding ability to TEAD protein, the compound of general formula (I) of the present invention is Z is -CH2-, -NH-, -O-; R 1 is as described in the context of this disclosure; R 2 is as described in the context of this disclosure; Or, R 1 and R 2 are linked to form a 4-membered or 6-membered ring, or at least one hydrogen atom is bonded to R 1-1 forming a 4-membered or 6-membered ring substituted with R 1-1 are independently as described in the context of the present disclosure; (preferably, R 1 and R 2 are combined with each other TIFF2025530470000118.tif18170) Ring A is TIFF2025530470000119.tif23170; Ring B is a 5-membered nitrogen-containing heterocycle, a 6-membered nitrogen-containing heterocycle, one hydrogen atom of which is methyl, TIFF2025530470000120.tif14170, or one hydrogen atom is methyl, TIFF2025530470000121.tif14170 is a substituted six-membered nitrogen-containing heterocycle; Here, the five-membered nitrogen-containing heterocycle is TIFF2025530470000122.tif15170The six-membered nitrogen-containing heterocycle is TIFF2025530470000123.tif15170 (More preferably, ring B is TIFF2025530470000124.tif42170) Ring C is phenyl, and at least one hydrogen is R 4 Phenyl substituted with C 5-8 Bridged bicycloalkyl, at least one hydrogen is R 4 C replaced with 5-12 Bridged bicycloalkyl, C 10-20 Bridged tricycloalkyl, at least one hydrogen is R 4 C replaced with 10-20 Bridged tricycloalkyl, 4- to 6-membered monocycloalkyl (preferably 6-membered monocycloalkyl), at least one hydrogen atom is R 4 4-6 membered monocycloalkyl (preferably where at least one hydrogen is R 4 6-membered monocycloalkyl substituted with 4 are independently as described in the context of this disclosure (preferably, R 4 is trifluoromethyl, pentafluorosulfanyl, fluorine, chlorine, bromine, -SCF3, -OCF3 or cyclopropane).

[0112] As used herein, the term "alkyl" refers to a straight- or branched-chain saturated monovalent hydrocarbon group, which may be optionally substituted with one or more substituents. In certain embodiments, an alkyl group has 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~12 pieces (C 1-12 ), 1~10 pieces (C 1-10 ) or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C3-15 ), 3~12 pieces (C 3-12 ) 、 3~10 pieces (C 3-10 ) or 3 to 6 (C 3-6 ) is a branched saturated monovalent hydrocarbon radical having carbon atoms. 1-6 and branch C 3-6 Alkyl is also referred to as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers), n-propyl, isopropyl, butyl (including all isomers), n-butyl, isobutyl, tert-butyl, pentyl (including all isomers), and hexyl (including all isomers). For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In one embodiment, the alkyl is an optionally substituted alkyl as described elsewhere herein.

[0113] As used herein, the term "cycloalkyl" refers to a cyclic, fully or partially saturated, bridged and / or unbridged hydrocarbon group or ring system, which may be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~12 pieces (C 3-12 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl as described elsewhere herein.

[0114] The term "monocycloalkyl" as used herein refers to a monocyclic cycloalkyl. In some embodiments of the present invention, the monocycloalkyl is cyclopropyl (equivalent to cyclopropane), cyclobutyl (equivalent to cyclobutane), cyclopentyl (equivalent to cyclopentane), or cyclohexyl (equivalent to cyclohexane).

[0115] As used herein, the term "bridged bicycloalkyl" refers to a ring system formed by bridging two monocycloalkyls. In some embodiments of the present invention, the bridged bicycloalkyl is bicyclo[1.1.1]pentanyl or bicyclo[2.2.2]octanyl. In some embodiments of the present invention, the bridged bicycloalkyl is optionally substituted with a substituent.

[0116] As used herein, the term "bridged tricycloalkyl" refers to a ring system formed by bridging three monocycloalkyls. In some embodiments of the present invention, the bridged tricycloalkyl is adamantyl. In some embodiments of the present invention, the bridged tricycloalkyl is optionally substituted with a substituent.

[0117] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring system formed by replacing at least one ring carbon atom with at least one heteroatom selected from N, O, and / or S(=O)m', where m' is an integer from 0 to 2. Examples include monocyclic heterocycloalkyl, spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl. Preferably, the heterocycloalkyl is a 3- to 20-membered heterocycloalkyl, more preferably, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl, and more preferably, the heterocycloalkyl is a 3- to 6-membered monocyclic heterocycloalkyl. The term "oxacycloalkyl" refers to a heterocycloalkyl where the heteroatom is O. The term "azacycloalkyl" refers to a heterocycloalkyl where the heteroatom is nitrogen. In some embodiments of the invention, a heterocycloalkyl is The file is TIFF2025530470000125.tif12170.

[0118] As used herein, the terms "aryl," "aryl ring," and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings are covalently connected and not fused), or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group in which at least one ring is aromatic, i.e., has a conjugated π-electron system. 6-14 "Aryl" refers to an aryl having 6 to 14 ring atoms, preferably C 6-10 In the present invention, C 6-14 The aryl includes a monocyclic aryl, a non-fused polycyclic aryl, and an aromatic fused polycyclic aryl, where an example of the monocyclic aryl is phenyl, and an example of the non-fused polycyclic aryl is biphenyl, etc.

[0119] As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic or polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S, and N. In one embodiment, each ring of a heteroaryl can have one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In certain embodiments, a heteroaryl refers to a bicyclic, tricyclic, or tetracyclic ring, in which one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated, or aromatic, may be carbocyclic, or may contain one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thiophenyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzothienyl, benzotriazolyl, benzoxazolyl, fluoropyridinyl, imidazopyridinyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolylpyridinyl, phthalazinyl, pteridinyl, pyridinopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, bisbenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenopyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents described elsewhere herein.

[0120] The term "5- or 6-membered monocyclic heteroaryl" as used herein refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m', where m' is an integer from 0 to 2. Specific examples of monocyclic heteroaryls include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine. The term "5- or 6-membered nitrogen-containing monocyclic heteroaryl" refers to a 5- or 6-membered monocyclic heteroaryl in which at least one ring atom is nitrogen.

[0121] The term "8-10-membered bicyclic heteroaryl" as used herein refers to a fused bicyclic heteroaryl having 8-10 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m' (where m' is an integer from 0 to 2). The fused bicyclic heteroaryl may be a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) formed by the fusion of a monocyclic aromatic ring (such as a phenyl group) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group formed by the fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). In some embodiments of the present invention, the 8-10-membered bicyclic heteroaryl is The file is TIFF2025530470000126.tif18170.

[0122] The term "alkoxy," as used herein, refers to a stable linear or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, 1 to 3) O atoms. Examples of alkoxy include, but are not limited to, -O-CH (methoxy), -O-CH-CH (ethoxy), -O-CH-CH-CH (n-propoxy), -O-CH-(CH) (isopropoxy), and -O-CH-CH-O-CH. In one embodiment, alkoxy is optionally substituted alkoxy, as described elsewhere herein.

[0123] As used herein, the term "alkylmercapto" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, 1 to 3) S atoms. Examples of alkylmercapto include -S-CH3, -S-CH2-CH3, -S-CH2-CH2-CH3, -S-CH-(CH3)2, and -S-CH2-CH2-S-CH3.

[0124] As used herein, the term "bond" refers to the chemically operable formation of a covalent bond between any two atoms within one or more groups. Chemically operable means that the covalent bond formed conforms to classical valence bond theory. In one embodiment of the present invention, -CHC (β) The β carbon atom in H3 TIFF2025530470000127.tif8170Nitrogen atoms bonded to each other In another embodiment of the present invention, the following is generated: TIFF2025530470000129.tif8170The β carbon atom and the methyl carbon atom are bonded to each other. Form TIFF2025530470000130.tif11170.

[0125] As used herein, the term "heteroaryl ketone group" refers to a group in which a carbonyl group is directly attached to a heteroaromatic ring. In one embodiment of the present invention, the heteroaryl ketone group is, for example, a pyridone group, e.g., The file is TIFF2025530470000131.tif18170.

[0126] As used herein, the term "amino" refers to -NH2.

[0127] As used herein, the term "hydroxy" refers to --OH.

[0128] As used herein, "-SO2-" means Points to TIFF2025530470000132.tif14170.

[0129] The term "benzyl" as used herein refers to -CH2-benzene.

[0130] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0131] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom may be replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur in aromatic groups. The term "optionally substituted" or "optionally substituted" means that the group may or may not be substituted, and unless otherwise specified, the type and number of substituents are optional as long as they are chemically feasible.

[0132] As used herein, "at least one hydrogen is replaced by a substituent" means that one hydrogen is replaced by a substituent, or multiple (e.g., 2, 3, or 4) hydrogens are replaced by the same or different substituents.

[0133] The above group is It is attached to the rest of the molecule through the ring atoms marked in TIFF2025530470000133.tif8170.

[0134] Pharmaceutical Composition Meanwhile, embodiments of the present invention further provide a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0135] As used herein, the term "stereoisomer" includes conformational and configurational isomers, where configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described herein may exist in stereoisomeric forms, and therefore encompass all possible stereoisomeric forms, including, but not limited to, cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, and the like. The compounds described herein may also exist in any combination or mixture of the aforementioned stereoisomers, such as mesoforms, racemates, or equal mixtures of atropisomers. Examples include single enantiomers, single diastereomers or mixtures thereof, or single atropisomers or mixtures thereof. When a compound described herein contains an olefinic double bond, cis isomers, trans isomers, and any combinations thereof are included unless otherwise specified. The atropisomers of the present invention are stereoisomers that have axial or planar chirality due to restricted internal molecular rotation. As a pharmaceutical, a stereoisomer having excellent activity is preferred. The compound of general formula (I) has optical isomers due to asymmetric carbons, etc., but if necessary, a single isomer can be obtained by separating it by a method known in the art, such as crystallization or chiral chromatography.

[0136] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids and bases, as well as suitable organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, bisgluconate, dodecyl sulfate, ethanesulfonate, formate, fenugreek, glucoheptanoate, glycerophosphate, gluconate, hemisulfinate, heptanoate, caproate, hydriodate, 2-hexadextrin, ethanesulfonate ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts (where applicable) include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0137] As used herein, the terms "solvate" and "solvate" refer to a compound of the present invention combined with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid and the like. Solvates include stoichiometric and non-stoichiometric solvates. Certain compounds of the present invention can exist in both solvated and unsolvated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.

[0138] Purpose Meanwhile, embodiments of the present invention further provide the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of the present invention for the following uses: (i) binds to TEAD; preferably binds to the palmitoyl pocket of TEAD; (ii) inhibition of TEAD transcript levels; (iii) inhibition / blocking of YAP-TEAD binding; (iv) inhibition / blocking of YAP-TEAD transcriptional function; (v) regulation of the Hippo signaling pathway; and (vi) prevention and / or treatment of diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway, and / or (vii) The manufacture of a pharmaceutical for preventing and / or treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or impairment of the Hippo signaling pathway.

[0139] Treatment method Meanwhile, an embodiment of the present invention further provides a method for treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or impairment of the Hippo signaling pathway, the method comprising the steps of: administering to a subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; Alternatively, administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject.

[0140] As used herein, the term "prevention" refers to preventing the onset, recurrence, or spread of a disease or condition, or one or more symptoms associated with the disease or condition. In one embodiment, the symptoms are known to those of skill in the art to be associated with the disease or condition being prevented. In certain embodiments, the term refers to administering a compound provided herein, with or without additional active agents, to a patient at risk of developing a disease or condition described herein prior to the onset of symptoms. The term includes both the suppression and alleviation of symptoms of a particular disease. In certain embodiments, patients with a family history of the disease are particularly considered candidates. Additionally, patients with a history of recurrence of symptoms may also be candidates for prevention.

[0141] As used herein, the term "treatment" refers to the eradication or amelioration of a disease or condition, or one or more symptoms associated with a disease or condition. In one embodiment, the symptoms are known to those of skill in the art to be associated with the disease or condition being treated. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or condition by administering one or more prophylactic or therapeutic agents to a subject suffering from the disease or condition. In some embodiments, the term refers to the administration of a compound of the present invention, with or without other additional active agents, after the onset of symptoms of a particular disease.

[0142] As used herein, the term "subject" is defined to include animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like.

[0143] The compounds of the invention are included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects to the patient being treated.

[0144] As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to provide a therapeutic effect in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with a disease or disorder. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic effect in the treatment or management of a disease or disorder. The term "therapeutically effective amount" includes an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of another therapeutic agent.

[0145] Preparation of compounds Meanwhile, the present invention also provides general synthetic routes for the compounds, including general synthetic routes I, II and III.

[0146] General synthetic route I: SM-1 reacts with SM-2 in the presence of NaH or K2CO3 as a base to undergo a nucleophilic aromatic substitution reaction to give Int-1. The Br atom of Int-1 is converted to a boronate ester using a Pd-catalyzed reaction with SM-3 to give Int-2. Int-2 then undergoes a Pd-catalyzed Suzuki reaction with an aromatic chloride or bromide, Int-3, to give Int-4. If Z in Int-4 is NH, it must be protected with Boc to give Int-5. The nitro group in Int-5 is then reduced to an amino group to give Int-6. The amino group in Int-6 is diazotized with isoamyl nitrite and iodinated with copper iodide to give Int-7. The iodide Int-7 reacts with a dialkylphosphine oxide, SM-4, to undergo a Pd-catalyzed carbon-phosphorus coupling reaction to give Int-8. When Z of Int-8 is protected with Boc, the final compound can be obtained by a further step of deprotecting Boc with TFA. TIFF2025530470000134.tif168170

[0147] General synthetic route II: According to general synthetic route I, TIFF2025530470000135.tif10170 is used as Int-3 to synthesize Int-8-1. The methylthio group of Int-8-1 is oxidized to methyl sulfone using mCPBA to obtain Int-9. SM-5 reacts with Int-9 in the presence of NaH or K2CO3 as a base to give Int-10 via a nucleophilic aromatic substitution reaction. When Z of Int-10 is protected with Boc, the final compound can be obtained by a further step of deprotecting Boc with TFA. TIFF2025530470000136.tif83170

[0148] General synthetic route III: SM-6 undergoes a carbon-phosphorus coupling reaction with dimethylphosphine oxide under Pd-catalyzed conditions, followed by a nucleophilic aromatic substitution reaction with SM-1 in the presence of NaH or K2CO3 as a base to give Int-11. The cyano group of Int-11 reacts with hydroxylamine, and the resulting condensation product is treated with acetyl chloride in pyridine to close the oxadiazole heterocycle to give the final compound. TIFF2025530470000137.tif79170

[0149] In certain embodiments, the subject is a human being. In order to clarify the objectives, technical solutions, and advantages of the embodiments of the present invention, the present invention will be further described below based on specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods that do not specify specific experimental conditions generally follow conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are percentages and parts by weight. Experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0150] Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be noted that the terminology used herein is intended to describe specific embodiments only and is not intended to limit the exemplary embodiments of the present application.

[0151] Example 1: Synthesis and characterization of compound 8 TIFF2025530470000138.tif127170

[0152] Synthesis of intermediate Int-1 Compound SM-1 (8.06 g, 50.00 mmol, 1 eq) was dissolved in DMAc (100 mL) and NaH (4.0 g, 100.00 mmol, 2 eq) was added at 0 °C. After the addition was complete, the mixture was stirred for 0.5 h. Compound SM-2 (11.0 g, 50.00 mmol, 1 eq) was dissolved in DMAc (15 mL) and added at 0 °C. After the addition was complete, the mixture was heated to 130 °C and stirred overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, 100 mL of saturated aqueous NH4Cl and 150 mL of EA were added, filtered, and the filtrate was separated to obtain the organic phase. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column (PE:EA = 15:1) to obtain intermediate 3 (3.6 g, purity 89%, yield 17.74%) as a yellow solid. LCMS [M+H] + =361 / 363.

[0153] Synthesis of intermediate Int-2 Compound Int-1 (1 g, 2.77 mmol, 1 eq), compound SM-3 (0.844 g, 3.32 mmol, 1.2 eq), Pd(dppf)Cl2 (0.2 g, 0.277 mmol, 0.1 eq), and potassium acetate (0.54 g, 5.54 mmol, 2 eq) were added sequentially to 1,4-dioxane (10 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. After monitoring for reaction completion by LCMS, the mixture was cooled to room temperature, 100 mL of water and 150 mL of EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 4 (1.7 g, crude product) as a black solid. LCMS [M+H] + =409.

[0154] Synthesis of intermediate Int-3 Compound SM-4 (2.2 g, 11.37 mmol, 1 eq) and compound SM-5 (0.84 g, 11.37 mmol, 1 eq) were dissolved in THF (10 mL), and potassium tert-butoxide (1.4 g, 12.51 mmol, 1.1 eq) was dissolved in THF (10 mL). The mixture was added dropwise to the reaction system at -50 °C. After the addition was complete, the mixture was stirred at -50 °C for 1 h. After monitoring the reaction completion by LCMS, 100 mL of saturated aqueous ammonium chloride was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and back-extracted to give intermediate 5 (0.56 g, 99% purity, 26.12% yield) as a white solid. LCMS [M+H] + =187.

[0155] Synthesis of intermediate Int-4 Intermediate Int-2 (1.7 g, 2.77 mmol, crude product), Intermediate Int-3 (0.517 g, 2.77 mmol, 1 eq), Pd(dppf)Cl2 (0.2 g, 0.277 mmol, 0.1 eq), and cesium carbonate (1.8 g, 5.54 mmol, 2 eq) were added sequentially to a mixture of DMF (15 mL) and water (3 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. The reaction was monitored for completion by LCMS, cooled to room temperature, and 100 mL of water and 150 mL of EA were added. The filtrate was separated to obtain an organic phase, which was dried over anhydrous sodium sulfate. The organic phase was concentrated and further purified by silica gel column (DCM:MeOH = 10:1) to obtain Intermediate Int-4 (0.5 g, purity 89%, yield 37.18%) as a pale yellow solid. LCMS[M+H] + =433.

[0156] Synthesis of intermediate Int-5 Intermediate Int-4 (500 mg, 1.16 mmol, 1 eq), BocO (505 mg, 2.31 mmol, 2 eq), and DMAP (71 mg, 0.578 mmol, 0.5 eq) were dissolved in THF (8 mL) and stirred under reflux for 3 h. After completion of the reaction was monitored by LCMS, 100 mL of aqueous solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a silica gel column (DCM:MeOH = 12:1) to give intermediate Int-5 (540 mg, 89% purity, 78% yield) as a pale yellow solid.

[0157] Synthesis of intermediate Int-6 Intermediate Int-5 (540 mg, 1.01 mmol, 1 eq), Zn powder (398 mg, 6.06 mmol, 6 eq), and solid ammonium chloride (542 mg, 10.14 mmol, 10 eq) were dissolved in a mixture of EtOH (10 mL) and water (2 mL) and stirred under reflux for 2 h. After completion of the reaction monitored by LCMS, 50 mL of aqueous solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a silica gel column (DCM:MeOH = 10:1) to give intermediate Int-6 (400 mg, purity 73.7%, yield 57.85%) as a pale yellow solid.

[0158] Synthesis of intermediate Int-7 Intermediate Int-6 (400 mg, 0.796 mmol, 1 eq), isoamyl nitrite (112 mg, 0.955 mmol, 1.2 eq), and cuprous iodide (227 mg, 1.19 mmol, 1.5 eq) were dissolved in acetonitrile (8 mL) and stirred under reflux for 2 h. After completion of the reaction was monitored by LCMS, 50 mL of aqueous solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a silica gel column (DCM:MeOH = 9:1) to give intermediate Int-7 (120 mg, purity 84.5%, yield 20.77%) as a pale yellow solid.

[0159] Synthesis of intermediate Int-8 Intermediate Int-7 (120 mg, 0.196 mmol, 1 eq), compound SM-6 (23 mg, 0.293 mmol, 1.5 eq), Pd(dba) (36 mg, 0.039 mmol, 0.2 eq), XantPhos (23 mg, 0.039 mmol, 0.2 eq), and TEA (39 mg, 0.391 mmol, 2 eq) were added sequentially to DMF (5 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. The reaction was monitored for completion by LCMS, cooled to room temperature, added 30 mL of water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by TLC (DCM:MeOH = 10:1) to give intermediate Int-8 (70 mg, purity 91%, yield 28.89%) as a pale yellow solid.

[0160] Synthesis of compound 8 Intermediate Int-8 (70 mg, 0.12 mmol, 1 eq) was dissolved in DCM (4 mL), TFA (1 mL) was added at 0 °C, and the mixture was reacted at 25 °C for 1 h. After completion of the reaction, the mixture was cooled to 0 °C and diluted with water (30 mL). Saturated aqueous sodium carbonate solution was added dropwise to adjust the mixture to alkaline. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonia / acetonitrile system) and lyophilized to give compound 8 (25.0 mg, 0.054 mmol, purity 99.0%, yield 45%) as a yellow solid. LCMS [M+1] + =463.8. 1 H-NMR(400MHz,DMSO-d6)δ 11.35(s,1H),8.73(d,J=6.0Hz,1H),8.68(dd,J=12.4,1.6Hz,1H),7.76-7.70(m,1H),7.67(d,J=8.4Hz,2H),7.54(dd,J=8.4,2.4Hz, 1H),7.45(d,J=8.8Hz,2H),7.02(d,5.6Hz,1H),5.79-5.73(m,1H),4.95(t,J=7.2Hz,2H),4.69-4.66(m,2H),1.67(d,J=13.2Hz,6H).

[0161] Example 2: Synthesis and characterization of compound 1 TIFF2025530470000139.tif114170

[0162] Synthesis of intermediate Int-1 Intermediate Int-2 (2 g, 4.9 mmol, 1 eq) in Example 1, compound SM-1 (1.5 g, 9.8 mmol, 2 eq), Pd(dppf)Cl 2( A three-neck flask was charged with CsCO (3.2 g, 9.8 mmol, 2 eq). The atmosphere was replaced with nitrogen, and then DMF (20 mL) and H2O (4 mL) were added. The mixture was reacted at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (150 mL), washed with water (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate Int-1 (830 mg, 2.3 mmol, purity 92%, yield 46.89%) as a yellow solid. LCMS [M+H] + =363.

[0163] Synthesis of intermediate Int-2 Intermediate Int-1 (830 mg, 2.3 mmol, 1 eq), BocO (1 g, 4.6 mmol, 2 eq), and DMAP (140 mg, 1.1 mmol, 0.5 eq) were dissolved in THF (20 mL) and refluxed at 70 °C for 16 h. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL), washed with 1 mol / L aqueous hydrochloric acid (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give Intermediate Int-2 (550 mg, 1.2 mmol, 91% purity, 51.54% yield) as a yellow oil. LCMS [M+H] + =462.9.

[0164] Synthesis of intermediate Int-3 Intermediate Int-2 (550 mg, 1.2 mmol, 1 eq) was dissolved in EtOH (10 mL), THF (2 mL), and HO (2 mL). Zn powder (630 mg, 9.6 mmol, 8 eq) and NHCl (650 mg, 12 mmol, 10 eq) were added, and the mixture was refluxed at 70 °C for 16 h. Zn powder was added twice every 3 h (630 mg x 2). After completion of the reaction, the reaction solution was filtered through Celite. The filtrate was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give intermediate Int-3 (300 mg, purity 90%, 0.7 mmol, yield 57.47%) as a yellow oil. LCMS [M-Boc] + =333.2.

[0165] Synthesis of intermediate Int-4 Intermediate Int-3 (300 mg, 0.7 mmol, 1 eq) and SM-2 (90 mg, 0.8 mmol, 1.1 eq) were dissolved in MeCN (15 mL), and CuI (200 mg, 1.05 mmol, 1.5 eq) was added under nitrogen protection. The mixture was reacted at 70 °C for 2 hours. After completion of the reaction, it was cooled to room temperature and diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1) to give intermediate Int-4 (180 mg, 0.33 mmol, 47.74% yield) as a yellow oil. LCMS [M+H] + =543.7.

[0166] Synthesis of intermediate Int-5 Under nitrogen protection, XantPhos (12 mg, 0.02 mmol, 0.05 eq), Pd(dba)2 (12 mg, 0.02 mmol, 0.05 eq), and TEA (100 mg, 1 mmol, 3 eq) were dissolved in anhydrous DMF (5 mL). The mixture was reacted at room temperature for 20 min. Next, intermediate Int-4 (180 mg, 0.33 mmol, 1 eq) and SM-3 (105 mg, 0.5 mmol, 1.5 eq) were added and reacted at 110 °C for an additional 16 h. After completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted with water (50 mL), and the aqueous layer was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain intermediate Int-5 (80 mg, 0.13 mol, purity 90%, yield 38.8%) as a yellow solid. LCMS [M+H] + =625.5.

[0167] Synthesis of intermediate Int-6 Intermediate Int-5 (80 mg, 0.13 mmol, 1 eq) was dissolved in MeOH (5 mL) at room temperature, and Pd / C (10 mg) and concentrated HCl (0.2 mL) were added. The mixture was then reacted under a hydrogen balloon for 16 hours. After completion of the reaction, the mixture was filtered and rotary dried to give intermediate Int-6 (45 mg, 0.08 mol, 90% purity, 65.71% yield) as a yellow solid, which was used directly in the next reaction without further purification. LCMS [M+H] + =534.9.

[0168] Synthesis of Compound 1 Intermediate Int-6 (40 mg, 0.08 mmol, 1 eq) was dissolved in DCM (3.5 mL), TFA (1.5 mL) was added, and the mixture was reacted at 25 °C for 1 h. After completion of the reaction, the mixture was cooled to 0 °C, diluted with water (30 mL), and adjusted to alkaline by dropwise addition of saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonia / acetonitrile system) and lyophilized to give compound 1 (16.2 mg, 0.037 mmol, purity 96.45%, yield 46.25%) as a yellow solid. LCMS [M+H] + =434.9. 1 H-NMR(400MHz,DMSO-d6)δ 10.78(s,1H),7.99(d,J=11.2Hz,1H),7.83(d,J=10.0Hz,2H),7.59(d,J=8.8Hz,2H),7.53-7.50(m,2H),7.3 0(d,J=8.8Hz,2H),3.73(s,3H),3.32-3.02(m,2H),2.96-2.87(m,2H),2.17-2.13(m,2H),1.80-1.76(m2H).

[0169] Example 3: Synthesis and characterization of compound 9 TIFF2025530470000140.tif228170

[0170] 1) Under N2 protection, Int-2 from Example 1, SM-1, Pd(dppf)Cl2, Na2CO3 were added to dioxane and H2O. 2) The reaction was carried out at 100°C for 3 hours and monitored by TLC. 3) Cool to room temperature. 4) The reaction solution was rotary dried, passed through a column (PE:EA=3:1) and rotary dried to obtain 5.5 g (92.1%) of intermediate Int-1 as a yellow solid.

[0171] TIFF2025530470000141.tif84170

[0172] 1) Int-1, Boc2O, and DMAP were added to THF. 2)80 o The reaction was allowed to proceed at C for 16 hours and monitored by TLC. 3) The reaction solution was rotary dried, passed through a column (PE:EA=3:1) and rotary dried to obtain 4.2 g (61.3%) of intermediate Int-2 as a white solid.

[0173] TIFF2025530470000142.tif90170

[0174] 1) Int-2, Zn, and NH4Cl were added to EtOH and H2O. 2)30 o The reaction was carried out at C for 16 hours and monitored by TLC. 3) The reaction solution was rotary dried, passed through a column (PE:EA=1:1) and rotary dried again to obtain 2.7 g (68.3%) of intermediate Int-3 as a yellow compound.

[0175] TIFF2025530470000143.tif84170

[0176] 1) Add Int-3 to acetonitrile and o Cooled to C. 2) SM-2 was added. 3)25 o C for 2 hours. 4) CuI was added. 5)70 o The reaction was allowed to proceed at C for 2 hours and monitored by TLC. 6) The reaction solution was rotary dried, passed through a column (PE:EA=3:1) and rotary dried again to obtain 1.2 g (36.1%) of intermediate Int-4 as a yellow compound.

[0177] TIFF2025530470000144.tif97170

[0178] 1) Int-4, SM-3, Pd2(dba)3, Xantphos, and TEA were added to dioxane. 2)70o The reaction was carried out at C for 4 hours and monitored by TLC. 3) The reaction solution was rotary dried, passed through a column (DCM:MeOH=10:1) and rotary dried to give 0.95 g (86.5%) of intermediate Int-5 as a yellow compound.

[0179] TIFF2025530470000145.tif78170

[0180] 1) Int-5 and mCPBA were added to DCM. 2)25 o The reaction was allowed to proceed at C for 16 hours and monitored by TLC. 3) The reaction mixture was rotary dried and passed through a column (DCM:MeOH=10:1) to give 480 mg (47.7%) of intermediate Int-6 as a pale yellow solid.

[0181] TIFF2025530470000146.tif85170

[0182] 1) Int-6, SM-4, and K2CO3 were added to DMF. 2)25 o The reaction was carried out at C for 1 hour and monitored by TLC. 3) The reaction mixture was rotary dried and passed through a column (DCM:MeOH=10:1) to give 125 mg (82.3%) of intermediate Int-7 as a pale yellow compound.

[0183] TIFF2025530470000147.tif79170

[0184] 1) Int-7, TFA was added to DCM. 2)25 o The reaction was allowed to proceed at C for 1 hour and monitored by TLC. 3) The reaction mixture was rotary dried and passed through a column (DCM:MeOH=10:1) to give 34.0 mg (34.3%) of Compound 9 as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 11.91(s,1H),8.86(dd,J=12.3,2.0Hz,1H),8.34(d,J=6.1Hz,1H),7.72-7.63(m,3H),7.54(dd,J=8.5,2.5Hz,1H),7.43(d,J=8.4Hz,2H),6.52(br s,1H),5.10(d,J=13.6Hz,1H),4.45(br s,1H),3.84-3.45(m,3H),2.58-2.53(m,1H),2.15-2.02(m,1H),2.01-1.90(m,1H),1.66(s,3H),1.63(s,3H).

[0185] Example 4: Synthesis and characterization of compound 10 TIFF2025530470000148.tif127170

[0186] 1) Int-6 from Example 3, SM-1, K2CO3 were added to DMF. 2)25 o The reaction was carried out at C for 1 hour and monitored by TLC. 3) The reaction solution was rotary dried, passed through a column (DCM:MeOH=10:1) and rotary dried again to obtain 130 mg (85.6%) of intermediate Int-1 as a pale yellow compound.

[0187] TIFF2025530470000149.tif79170

[0188] 1) Int-1, TFA was added to DCM. 2)25 o The reaction was allowed to proceed at C for 1 hour and monitored by TLC. 3) The reaction solution was rotary dried, passed through a column (DCM:MeOH=10:1) and rotary dried to obtain 62.3 mg (62.8%) of Compound 10 as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 11.91(s,1H),8.86(dd,J=12.3,2.0Hz,1H),8.34(d,J=6.1Hz,1H),7.72-7.63(m,3H),7.54(dd,J=8.5,2.5Hz,1H),7.43(d,J=8.4Hz,2H),6.52(br s,1H),5.10(d,J=13.6Hz,1H),4.45(br s,1H),3.84-3.45(m,3H),2.58-2.53(m,1H),2.15-2.02(m,1H),2.01-1.90(m,1H),1.66(s,3H),1.63(s,3H).

[0189] Example 5: Synthesis and characterization of compound 2 According to general synthetic route I, TIFF2025530470000150.tif27170 is Int-2, Compound 2 was synthesized using TIFF2025530470000151.tif15170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =471.

[0190] Example 6: Synthesis and characterization of compound 3 According to general synthetic route I, TIFF2025530470000152.tif27170 is Int-2, Compound 3 was synthesized using TIFF2025530470000153.tif15170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =473.

[0191] Example 7: Synthesis and characterization of compound 4 TIFF2025530470000154.tif58170

[0192] Synthesis of intermediate A-2: The starting materials A-1 (500 mg, 1.79 mmol), Pd2(dba)3 (164 mg, 0.18 mmol), XantPhos (207 mg, 0.36 mmol), dimethylphosphine oxide (167 mg, 2.14 mmol), and TEA (271 mg, 2.68 mmol) were added sequentially to dioxane (8 mL), purged with nitrogen, and stirred overnight at room temperature. 50 mL of water was added, followed by extraction with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified by flash column chromatography using DCM-MeOH (0-10%) to give intermediate A-2 (300 mg, 73.00% yield) as a red solid. LCMS: m / z = 231.1 (M + H) + ,ESI)

[0193] Synthesis of intermediate A-3: Compound A-2 (300 mg, 1.30 mmol) was dissolved in DMSO (5 mL) and p-trifluoromethylbenzylamine (457 mg, 2.61 mmol) was added. After the addition was complete, the mixture was heated to 60 °C and reacted for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column with DCM:MeOH (0-10%) (1% TEA) to obtain intermediate A-3 (340 mg, 67.70% yield) as a yellow solid. LCMS: m / z = 386.1 (M+H) + ,ESI)

[0194] Synthesis of intermediate A-4: To a solution of compound A-3 (300 mg, 0.78 mmol) in ethanol (5 mL), hydrazine hydrate (1.01 g, 20.24 mmol) was added. After the addition was complete, the mixture was heated to 100°C and reacted for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to give intermediate A-4 (200 mg, 66.67% yield) as a white solid. This was used directly in the next reaction without further purification. LCMS: m / z = 386.1 (M+H + ,ESI)

[0195] Synthesis of compound 4: To a suspension of compound A-4 (30 mg, 0.08 mmol) and ammonium chloride (1 mg, 0.02 mmol) in ethanol (1 mL) was added triethyl orthoacetate (38 mg, 0.23 mmol). After the addition was complete, the mixture was heated to 90°C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated, extracted with EA, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated, and then purified by preparative TLC using DCM:MeOH (10%) to give compound 4 (3.5 mg, 10.98% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.37(t,J=6.1Hz,1H),8.12(dd,J=11.8,1.9Hz,1H),7.71(d,J=8.2Hz,2H),7.64-7.56(m,3H ),6.84(dd,J=8.8,2.2Hz,1H),4.79(d,J=6.0Hz,2H),2.62(s,3H),1.60(s,3H),1.57(s,3H). LCMS:m / z=410.1(M+H + ,ESI).

[0196] Example 8: Synthesis and characterization of compound 5 TIFF2025530470000155.tif55170

[0197] Synthesis of intermediate A-2: Starting material A-1 (500 mg, 2.02 mmol), Pd2(dba)3 (185 mg, 0.20 mmol), XantPhos (234 mg, 0.40 mmol), dimethylphosphine oxide (190 mg, 2.43 mmol), and TEA (307 mg, 3.04 mmol) were added sequentially to dioxane (8 mL), purged with nitrogen, and stirred overnight at room temperature. 50 mL of water was added, followed by extraction with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified by flash column chromatography using DCM-MeOH (0-10%) to give intermediate A-2 (300 mg, 75.17% yield) as a red solid. LCMS: m / z = 198.0 (M + H) + ,ESI)

[0198] Synthesis of intermediate A-3: Compound A-2 (300 mg, 1.52 mmol) was dissolved in DMSO (5 mL) and p-trifluoromethylbenzylamine (533 mg, 3.04 mmol) was added. After the addition was complete, the mixture was heated to 100 °C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column using DCM:MeOH (0-10%) (1% TEA) to give intermediate A-3 (600 mg, 111.92% yield) as a yellow solid. LCMS: m / z = 353.1 (M+H) + ,ESI)

[0199] Synthesis of intermediate A-4: Sodium carbonate (481 mg, 4.54 mmol) was added to a suspension of compound A-3 (400 mg, 1.14 mmol) and hydroxylamine hydrochloride (394 mg, 5.68 mmol) in ethanol (15 mL). After the addition was complete, the mixture was heated to 80°C and reacted for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, evaporated to dryness, extracted with EA, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate A-4 (400 mg, 88.22% yield) as a yellow solid. This was used directly in the next reaction without further purification. LCMS: m / z = 400.1 (M+H + ,ESI)

[0200] Synthesis of compound 5: Acetyl chloride (118 mg, 1.50 mmol) was added to a solution of compound A-4 (400 mg, 1.14 mmol) in pyridine (5 mL) under ice bath conditions. After the addition was complete, the mixture was heated to 100 °C and reacted for 6 hours. After the reaction was complete, the mixture was cooled to room temperature. An appropriate amount of water was added to quench the reaction. The mixture was directly purified on a C18 column using water:acetonitrile (0-50%) (0.11% formic acid) to obtain compound 5 (70 mg, 17.07% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.36(dd,J=11.9,1.9Hz,1H),7.71(d,J=8.1Hz,2H),7.67-7.62(m,1H),7.57(dd,J=8.2,5.8Hz, 3H),6.79(dd,J=8.7,2.3Hz,1H),4.77(d,J=6.0Hz,2H),2.71(s,3H),1.59(s,3H),1.56(s,3H). LCMS:m / z=410.1(M+H + ,ESI).

[0201] Example 9: Synthesis and characterization of compound 6 According to general synthetic route III: Compound 6 was synthesized using TIFF2025530470000156.tif11170 as SM-1. LCMS [M+H] + =397.

[0202] Example 10: Synthesis and characterization of compound 7 According to general synthetic route I, TIFF2025530470000157.tif27170 as Int-2, Compound 7 was synthesized using TIFF2025530470000158.tif15170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =473.

[0203] Example 11: Synthesis and characterization of compound 11 According to general synthetic route I, TIFF2025530470000159.tif27170 is Int-2, Compound 11 was synthesized using TIFF2025530470000160.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =412.

[0204] Example 12: Synthesis and characterization of compound 12 According to general synthetic route I, TIFF2025530470000161.tif27170 is Int-2, Compound 12 was synthesized using TIFF2025530470000162.tif14170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =441.

[0205] Example 13: Synthesis and characterization of compound 13 According to general synthetic route II, TIFF2025530470000163.tif28170 as Int-8-1, Compound 13 was synthesized using TIFF2025530470000164.tif10170SM-5. LCMS [M+H] + =464. 1 H-NMR(400MHz,DMSO-d6)δ 11.29(s,1H),8.75(d,J=6.0Hz,1H),8.70(dd,J=12.4,2.0Hz,1H),7.74-7.69(m,1H),7.63-7.57(m,3H),7.41-7.39(m,2H) ),7.02(d,J=6.0Hz,1H),5.81-5.75(m,1H),4.97(t,J=7.2Hz,2H),4.70(dd,J=8.0,5.6Hz,2H),1.68(s,3H),1.63(s,3H).

[0206] Example 14: Synthesis and characterization of compound 14 According to general synthetic route II, TIFF2025530470000165.tif30170 as Int-8-1, Compound 14 was synthesized using TIFF2025530470000166.tif10170SM-5. LCMS [M+H] + =509.

[0207] Example 15: Synthesis and characterization of compound 15 TIFF2025530470000167.tif29170

[0208] Step 1: Synthesis of Compound 3 Compound 1 (3 g, 10.07 mmol), compound 2 (1.91 g, 10.07 mmol), DBU (3.07 g, 20.14 mmol), and anhydrous copper acetate (915 mg, 5.03 mmol) were added to acetonitrile (20 mL), and the mixture was further filtered with 4A molecular sieves, purged with oxygen three times, and stirred at 25 °C for 16 h. After filtration, concentration, and column purification (pure PE), the product, brown liquid compound 3 (570 mg, 1.29 mmol, 12.81% yield), was obtained.

[0209] Step 2: Synthesis of Compound 5 Compound 3 (1.7 g, 3.85 mmol), compound 4 (451 mg, 5.77 mmol), Pd2dba3 (353 mg, 384.60 μmol), Xantphos (446 mg, 769.21 μmol), and triethylamine (1.17 g, 11.54 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), purged with nitrogen three times, and reacted at 110 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give the product, compound 5 (800 mg, 2.04 mmol, 33.72% yield, 63.64% purity), as a brown solid. LCMS [M+1] + =392.0.

[0210] Step 3: Synthesis of compound 15 Compound 5 (100 mg, 255.00 μmol), compound 6 (77 mg, 306.01 μmol), cesium carbonate (250 mg, 765.01 μmol), and PdCl(dppf) (19 mg, 25.50 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and reacted at 90 °C under nitrogen protection for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparative HPLC to give the product, compound 15 (38 mg, 82.92 μmol, 32.52% yield, 95.66% purity), as an off-white solid. LCMS [M+1] + =435.8. 1H-NMR(400MHz,DMSO-d6)δ 8.23(d,J=41.2Hz,2H),7.83(d,J=15.0Hz,2H),7.61-7.40(m,4H),6.96(s,2H),5.56(s,1H),4.96-4.76(m,4H),1.65(d,J=13.4Hz,6H).

[0211] Example 16: Synthesis and characterization of compound 16 TIFF2025530470000168.tif29170

[0212] Step 1: Synthesis of Compound 3 Compound 1 (3 g, 10.07 mmol), compound 2 (1.91 g, 10.07 mmol), DBU (3.07 g, 20.14 mmol), and anhydrous copper acetate (915 mg, 5.03 mmol) were added to acetonitrile (20 mL), and the mixture was further filtered with 4A molecular sieves, purged with oxygen three times, and stirred at 25 °C for 16 h. After filtration, concentration, and column purification (pure PE), the product, brown liquid compound 3 (570 mg, 1.29 mmol, 12.81% yield), was obtained.

[0213] Step 2: Synthesis of Compound 5 Compound 3 (1.7 g, 3.85 mmol), compound 4 (451 mg, 5.77 mmol), Pd2dba3 (353 mg, 384.60 μmol), Xantphos (446 mg, 769.21 μmol), and triethylamine (1.17 g, 11.54 mmol) were added to N,N-dimethylformamide (5 mL), purged with nitrogen three times, and reacted at 110 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified using a column chromatography to obtain the product, compound 5 (800 mg, 2.04 mmol, 33.72% yield, 63.64% purity), as a brown solid. LCMS [M+1] + =392.0.

[0214] Step 3: Synthesis of compound 16 Compound 5 (100 mg, 0.255 mmol), compound 6 (81 mg, 0.306 mmol), cesium carbonate (250 mg, 0.765 mmol), and PdCl(dppf) (19 mg, 0.02550 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and reacted at 90 °C for 2 h. Diluted with water and extracted with ethyl acetate, the organic phase was concentrated and purified by preparative HPLC to give the product, compound 16 (10.6 mg, 0.0229 mmol, 8.97% yield, 97.98% purity), as an off-white solid. LCMS [M+1] + =449.9. 1 H NMR(400MHz,DMSO-d6)δ 8.31(s,1H),8.00(s,1H),7.86-7.70(m,2H),7.58(d,J=11.4Hz,2H),7.42(d,J=8. 0Hz, 3H), 6.88 (s, 2H), 4.53 (s, 2H), 4.32 (d, J=21.6Hz, 4H), 1.65 (d, J=13.4Hz, 7H).

[0215] Example 17: Synthesis and characterization of compound 17 TIFF2025530470000169.tif68170

[0216] Synthesis of intermediate 2 Compound 1 (3.60 g, 16.37 mmol, 1 eq) was dissolved in acetonitrile (50 mL), and K2CO3 (9.05 g, 65.47 mmol, 2 eq) and compound 1A (4.3 g, 24.55 mmol, 1 eq) were added at 25 °C. The mixture was then heated to 70 °C and stirred overnight. The reaction was monitored for completion by LCMS, cooled to room temperature, filtered, and the filtrate was added to 200 mL of saturated aqueous NH4Cl and 100 mL of EA. The filtrate was separated to obtain the organic phase, which was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was purified on a silica gel column (PE:EA = 10:1) to obtain intermediate 2 (3.0 g, 89% purity, 43.48% yield) as a yellow solid. LCMS [M+H] + =372.7 / 374.7.

[0217] Synthesis of intermediate 3 Intermediate 2 (6.5g, 17.33mmol, 1eq), B2Pin2 (4.84g, 19.06mmo, 1.2eq), Pd(dppf)Cl 2( (1.01 g, 1.39 mmol, 0.1 eq) and potassium acetate (6.93 g, 51.98 mmol, 2 eq) were added sequentially to 1,4-dioxane (100 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, and 100 mL of water and 150 mL of EA were added. The filtrate was separated to obtain the organic phase, which was dried over anhydrous sodium sulfate and concentrated to obtain Intermediate 3 (6 g, crude product) as a black solid. LCMS [M+H] + =422.9.

[0218] Synthesis of intermediate 4 Intermediate 3 (9.5 g, 22.50 mmol, crude), Intermediate 3A (4.34 g, 27.00 mmol, 1.2 eq), Pd(dppf)Cl2 (1.31 g, 1.8 mmol, 0.08 eq), and cesium carbonate (18.33 g, 56.25 mmol, 2.5 eq) were added sequentially to a mixture of 1,4-dioxane (150 mL) and water (30 mL). The mixture was purged with nitrogen, heated to 100 °C, and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, and 100 mL of water and 150 mL of EA were added. The mixture was filtered. The filtrate was separated to obtain an organic phase, which was extracted with EA. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give Intermediate 4 (8 g, crude) as a black solid. LCMS [M+H] + =420.8.

[0219] Synthesis of intermediate 5 Intermediate 4 (2 g, 4.76 mmol, 1 eq) was added to THF (30 mL), and BocO (2.08 g, 9.51 mmol, 2.19 mL, 2 eq) and DMAP (290.59 mg, 2.38 mmol, 0.5 eq) were added. The mixture was heated to reflux and stirred for 3 h. After completion of the reaction was monitored by LCMS, 100 mL of aqueous solution was added, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by silica gel column (PE:EA = 5:1) to give Intermediate 5 (1 g, 1.92 mmol, 40.34% yield, 90% purity) as a yellow solid. LCMS [M+H] + =520.8.

[0220] Synthesis of intermediate 6 Intermediate 5 (2.7 g, 5.19 mmol, 1 eq) was dissolved in a mixture of EtOH (30 mL) and water (6 mL), and Zn powder (2.71 g, 41.50 mmol, 6 eq) and solid ammonium chloride (2.77 g, 51.87 mmol, 10 eq) were added. The mixture was heated to reflux and stirred for 16 h. After monitoring the reaction completion by LCMS, it was filtered, added with 50 mL of aqueous solution, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a silica gel column (PE:EA = 1:1) to give Intermediate 6 (1.70 g, 3.12 mmol, 60.13% yield, 90% purity) as a pale yellow solid. LCMS [M+H + ]=490.8.

[0221] Synthesis of intermediate 7 Intermediate 6 (1 g, 2.04 mmol, 1 eq), isoamyl nitrite (286.58 mg, 2.45 mmol, 1.2 eq), and cuprous iodide (582.37 mg, 3.06 mmol, 1.5 eq) were added to acetonitrile (20 mL) and heated to reflux and stirred for 16 h. After monitoring the reaction completion by LCMS, 50 mL of aqueous solution was added, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (PE:EA = 15:1) to give Intermediate 7 (300 mg, 0.5 mmol, 24.51% yield, 91% purity) as a pale yellow solid. LCMS [M+H] + =601.8.

[0222] Synthesis of intermediate 8 Intermediate 7 (120 mg, 0.196 mmol, 1 eq), compound 4A (23 mg, 0.293 mmol, 1.5 eq), Pd2(dba)3 (36 mg, 0.039 mmol, 0.2 eq), XantPhos (23 mg, 0.039 mmol, 0.2 eq), and TEA (39 mg, 0.391 mmol, 2 eq) were added sequentially to DMF (5 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. After monitoring for completion by LCMS, the reaction was cooled to room temperature, added with 30 mL of water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by TLC (DCM:MeOH = 10:1) to give intermediate 8 (95 mg, 0.172 mmol, 91% purity, 87.84% yield) as a pale yellow solid. LCMS [M+H] + =551.8.

[0223] Synthesis of intermediate 9 Intermediate 8 (1.2 g, 2.18 mmol, 1 eq) was dissolved in DCM (20 mL), and a DCM solution of mCPBA (750.90 mg, 4.35 mmol, 2 eq) was added dropwise at 0° C. The mixture was stirred at 25° C. for 16 hours under nitrogen protection. The reaction was monitored for completion by LCMS. After washing with aqueous sodium bicarbonate, brine, drying over anhydrous sodium sulfate, and concentration, intermediate 9 (1.2 g, crude product) was obtained as a pale yellow solid. The product was used directly in the next reaction without further purification. LCMS [M+H] + =583.8.

[0224] Synthesis of intermediate 10 Intermediate 9 (1.6 g, 2.82 mmol, 1 eq) was dissolved in anhydrous THF (20 ml), purged with nitrogen three times, and NaH (246.76 mg, 6.17 mmol, 60% purity, 3 eq) was added in an ice bath, and the mixture was stirred for 0.5 h. Next, compound 5A (456.99 mg, 6.17 mmol, 3 eq) was added. After stirring at 0 °C for another 2 h and monitoring the reaction completion by LCMS, the reaction was quenched with 50 mL of ice water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give Intermediate 10 (1.2 g, crude product) as a pale yellow solid. LCMS [M+H] + =557.8.

[0225] Synthesis of compound 17 Intermediate 10 (1.6 g, 2.90 mmol, 1 eq) was dissolved in DCM (20 mL), TFA (5 mL) was added at 0 °C, and the mixture was reacted at 25 °C for 1 h. After completion of the reaction, the mixture was cooled to 0 °C, diluted with water (30 mL), and saturated aqueous sodium carbonate solution was added dropwise to adjust the mixture to alkaline. The aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic layer was washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by preparative HPLC (ammonia / acetonitrile system), and lyophilized to give compound 17 (565 mg, 0.98 mmol, purity 98.20%, yield 33.7%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 9.95(t,J=6.0Hz,1H),8.72-8.68(m,2H),7.73-7.71(m,2H),7.59-7.51(m,3H),6.96(d,J=5.6Hz,1H),6.75-6.72( m,1H),5.75-5.69(m,1H),4.96(t,J=7.2Hz,2H),4.74(d,J=6.0Hz,2H),4.70-4.67(m,2H),1.59(d,J=13.2Hz,6H). LCMS[M+H] + =477.8.

[0226] Example 18: Synthesis and characterization of compound 18 TIFF2025530470000170.tif30170

[0227] Synthesis of intermediate 10 Intermediate 9 (101.87 mg, 1.16 mmol, 1 eq, see the synthesis of compound 8) was dissolved in anhydrous THF (10 mL), purged with nitrogen three times, and NaH (86.72 mg, 2.17 mmol, 60% purity, 6 eq) was added under ice bath conditions. The mixture was stirred for 0.5 h. Next, a THF solution (5 mL) of compound 9A (456.99 mg, 6.17 mmol, 3 eq) was added. The reaction was continued for another 2 h at 0 °C. After completion of the reaction was monitored by LCMS, the reaction was quenched by adding 50 ml of ice water, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give intermediate 10 (1.2 g, crude product) as a pale yellow solid. LCMS [M+H] + =577.8.

[0228] Synthesis of compound 18 Intermediate 10 (200 mg, 346.30 μmol) was dissolved in a 30% TFA solution in DCM (10 mL), and the mixture was reacted at 25° C. for 2 hours. After completion of the reaction, the mixture was cooled to 0° C., diluted with EA (20 mL), and the mixture was adjusted to alkaline by dropwise addition of saturated aqueous sodium carbonate. The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (ammonia / acetonitrile system) and lyophilized to give compound 18 (66.7 mg, 139.71 μmol, purity 96.52%, yield 40.34%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.35(s,1H),8.79-8.75(m,1H),8.70(d,J=6.0Hz,1H),7.77-7.72(m,1H), 7.68(d,J=8.0Hz,2H),7.58-7.55(m,1H),7.46(d,J=8.0Hz,2H),6.95(d,J= 5.6Hz,1H),5.70-5.66(m,1H),4.00-3.96(m,1H),3.92-3.85(m,2H),3.81- 3.76(m,1H),2.35-2.28(m,1H),2.15-2.08(m,1H),1.67(d,J=13.2Hz,6H). LCMS[M+H] + =477.9.

[0229] Example 19: Synthesis and characterization of compound 19 According to general synthetic route II, TIFF2025530470000171.tif29170 as Int-8-1, Compound 19 was synthesized using TIFF2025530470000172.tif4170 as SM-5. LCMS [M+H] + =452.

[0230] Example 20: Synthesis and characterization of compound 20 TIFF2025530470000173.tif52170

[0231] Synthesis of intermediate 3 twenty five oIn step C, Xantphos (961.50 mg, 1.66 mmol) and Pd2(dba)3 (1.52 g, 1.66 mmol) were added to a 100 mL three-neck flask and flushed with nitrogen three times. Then, 1,4-dioxane (20 mL) and TEA (2.52 g, 24.93 mmol) were added. The mixture was reacted under nitrogen protection at 25 °C for 10 minutes. Compound 1 (5 g, 16.62 mmol) and compound 2 (1.30 g, 16.62 mmol) were then added and reacted for an additional 24 hours. LCMS confirmed the completion of the reaction mixture and the formation of the product. The mixture was diluted with 100 mL of ethyl acetate and washed with 50 mL of water and 50 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified using a silica gel column (eluent: dichloromethane:methanol = 10:1) to obtain intermediate 3 (2.20 g, 7.89 mmol, purity 90%, yield 47.47%) as a yellow oil. LCMS [M+1] + =251 / 253.

[0232] Synthesis of intermediate 5 Compound 4 (2.3 g, 5.65 mmol) was dissolved in 1,4-dioxane, purged with nitrogen, and NaH (637 mg, 15.93 mmol) was added at 0 ° C. and stirred at this temperature for 0.5 hours. Compound 3 (2 g, 7.97 mmol) was then added, and the reaction mixture was heated to 80 ° C. and stirred for 0.5 hours. After completion of the reaction was monitored by LCMS, the mixture was cooled to room temperature, 100 mL of ethyl acetate was added, and the mixture was washed with 100 mL of saturated aqueous ammonium chloride and 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate 5 (2.5 g, crude product) as a yellow oil. LCMS [M+1] + =407 / 409.

[0233] Synthesis of intermediate 7 Intermediate 5 (2.3 g, 5.65 mmol, crude product), compound 6 (1.72 g, 6.78 mmol), Pd(dppf)Cl (0.328 g, 0.452 mmol), and anhydrous potassium acetate (1.66 g, 16.95 mmol) were added sequentially to 1,4-dioxane (25 mL), purged with nitrogen, heated to 100 ° C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, 100 mL of water and 150 mL of EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 7 (2.5 g, crude product) as a black oil. LCMS [M + H + ]=455.

[0234] Synthesis of intermediate 9 Intermediate 7 (1.4 g, 3.08 mmol), compound 8 (0.594 g, 3.7 mmol), Pd(dppf)Cl2 (0.224 g, 0.308 mmol), and cesium carbonate (3.01 g, 9.25 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL), purged with nitrogen, heated to 100 °C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, 100 mL of water and 150 mL of EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column (DCM:MeOH = 10:1) to obtain intermediate 9 (0.73 g, 91% purity, 47.64% yield) as a pale yellow oil. LCMS [M+H + ]=453.

[0235] Synthesis of intermediate 10 Intermediate 9 (350 mg, 0.77 mmol) was dissolved in anhydrous dichloromethane (5 mL) and purged with nitrogen. mCPBA (267 mg, 1.55 mmol) was dissolved in anhydrous dichloromethane (5 mL) and slowly added to the reaction mixture using a syringe at 0 °C. After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 2 hours. After monitoring the completion of the reaction by LCMS, 100 mL of aqueous solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give Intermediate 10 (350 mg, crude product) as a pale yellow oil. LCMS [M+H +]=469.

[0236] Synthesis of compound 20 Compound 11 (166 mg, 2.24 mmol) was dissolved in anhydrous THF (5 mL), and NaH (166 mg, 2.24 mmol) was added at 0°C. The mixture was stirred at this temperature for 0.5 hours. Intermediate 10 (350 mg, 0.747 mmol) was dissolved in anhydrous THF (5 mL) and added to the reaction mixture, and the mixture was stirred at 0°C for another 2 hours. After monitoring the completion of the reaction by LCMS, 50 mL of aqueous ammonium chloride solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by preparative HPLC to give compound 20 (95 mg, purity 96.7%, yield 25.0%) as a pale yellow solid. LCMS [MH + ]=479. 1 H-NMR(400MHz,CDCl3)δ 8.63(d,J=6.0Hz,1H),8.03(dd,J=11.6,2.0Hz,1H),7.87-7.82(m,1H),7.63(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.14(dd,J=8. 8,1.6Hz,1H),6.77(d,J=6.0Hz,1H),5.57-5.51(m,1H),5.28(s,2H),4.88-4.85(m,2H),4.71-4.68(m,2H),1.75(d,J=12.8Hz,6H).

[0237] Example 21: Synthesis and characterization of compound 21 According to general synthetic route I, TIFF2025530470000174.tif27170 is Int-2, TIFF2025530470000175.tif10170 as Int-3, Compound 21 was synthesized using TIFF2025530470000176.tif9170 as SM-4. LCMS [M+H] + =434.

[0238] Example 22: Synthesis and characterization of compound 22 According to general synthetic route I, TIFF2025530470000177.tif27170 is Int-2, TIFF2025530470000178.tif10170 as Int-3, Compound 22 was synthesized using TIFF2025530470000179.tif10170 as SM-4. LCMS [M+H] + =481.

[0239] Example 23: Synthesis and characterization of compound 23 According to general synthetic route I, TIFF2025530470000180.tif27170 is Int-2, Intermediate 23-A was synthesized using TIFF2025530470000181.tif9170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =475,477.

[0240] TIFF2025530470000182.tif28170

[0241] Intermediate 23-A (57 mg, 0.1 mmol, 1 eq), 2-methyl-3-mercaptotetrahydrofuran (59 mg, 0.5 mmol, 5 eq), CuI (4 mg, 0.02 mmol, 0.2 eq), and potassium carbonate (69 mg, 0.5 mmol, 5 eq) were placed in a reaction tube, 0.5 mL of DMSO was added, the mixture was purged with nitrogen, and the mixture was stirred and heated in an oil bath at 100 °C for 24 h. After completion of the reaction, the reaction tube was cooled to room temperature, water was added to dilute the mixture, and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile system) and lyophilized to give Intermediate 23-B (16 mg, 0.026 mmol, purity 95.4%, yield 26%) as a brown solid. LCMS [M+H] + =513.

[0242] Intermediate 23-B (16 mg, 0.026 mmol, 1 eq) was dissolved in 0.5 mL of DCM and stirred. 75% mCPBA (18 mg, 0.078 mmol, 3 eq) was added while cooling in an ice-water bath. The mixture was allowed to warm to room temperature and stirred for 16 hours, after which the reaction was confirmed to be complete by LC-MS. 0.1 mL of TFA was added to the mixture and stirred for another hour. LC-MS confirmed that Boc had been completely removed. The mixture was diluted with water, and the aqueous layer was extracted with DCM (8 mL x 3). The combined organic layer was washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile system) and lyophilized to give compound 23 (4 mg, 0.0073 mmol, purity 97%, yield 28%) as a yellow solid. LCMS [M+H] + =545.

[0243] Example 24: Synthesis and characterization of compound 24 TIFF2025530470000183.tif26170

[0244] 2-Iodo-5-fluorothiophene (1 eq), dimethylphosphine oxide (1.5 eq), Pd2(dba)3 (0.2 eq), XantPhos (0.2 eq), and TEA (2 eq) were added sequentially to DMF, purged with nitrogen, heated to 100 °C, and stirred overnight. The reaction was monitored for completion by LC-MS, cooled to room temperature, diluted with water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by silica gel column chromatography to give intermediate 24-A (34% yield). LCMS [M+H] + =179.

[0245] TIFF2025530470000184.tif27170

[0246] p-Trifluoromethylaniline (1.5 eq) was dissolved in DMAc, and NaH (2 eq) was added at 0°C. After the addition was complete, the mixture was stirred for 0.5 hours. Intermediate 24-A (1 eq) was dissolved in DMAc and added at 0°C. After the addition was complete, the mixture was heated to 130°C and stirred overnight. After the reaction was monitored by LCMS, the mixture was cooled to room temperature, saturated aqueous NH4Cl and EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column to obtain intermediate 24-B (yield 23%) as a brown oil. LCMS [M+H] + =320.

[0247] TIFF2025530470000185.tif30170

[0248] Intermediate 24-B (1 eq) was dissolved in acetonitrile, stirred, and NBS (1.2 eq) was added at room temperature. The mixture was heated in an oil bath for 60 o The reaction was monitored for completion by LCMS, then cooled to room temperature, saturated aqueous NaHCO3 and EA were added, filtered, the filtrate was separated to obtain the organic phase, washed with brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and further purified by silica gel column to obtain intermediate 24-C (yield 57%) as a reddish-brown solid. LCMS [M+H] + =398,400.

[0249] TIFF2025530470000186.tif29170

[0250] Intermediate 24-C (1 eq), (BPin) (1.2 eq), Pd(dppf)Cl (0.1 eq), and potassium acetate (2 eq) were added sequentially to 1,4-dioxane, purged with nitrogen, heated to 100°C, and stirred overnight. Completion of the reaction was monitored by LCMS, and then cooled to room temperature. Water and EA were added, filtered, and the filtrate was separated to obtain an organic phase, which was dried over anhydrous sodium sulfate and concentrated to obtain a crude product of Intermediate 24-D as a black solid.

[0251] The crude product of intermediate 24-D, intermediate Int-3 (1 eq), Pd(dppf)Cl2 (0.1 eq), and cesium carbonate (2 eq) were added sequentially to a 5:1 mixture of DMF and water, purged with nitrogen, heated to 100 °C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, water and EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified by silica gel column chromatography and preparative HPLC to obtain compound 24 as a pale brown solid. LCMS [M+H] + =470.

[0252] Example 25: Synthesis and characterization of compound 25 According to general synthetic route I, TIFF2025530470000187.tif27170 is Int-2, Compound 25 was synthesized using TIFF2025530470000188.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =464.

[0253] Example 26: Synthesis and characterization of compound 26 TIFF2025530470000189.tif31170

[0254] According to general synthetic route I, TIFF2025530470000190.tif10170 is SM-1, Intermediate 26-A was synthesized using TIFF2025530470000191.tif10170 as Int-3 and dimethylphosphine oxide as SM-4.

[0255] Intermediate 26-A (1 eq) was dissolved in DMF, and NBS (1.2 eq) was added with stirring. oC overnight. After the completion of the reaction was monitored by LCMS, it was cooled to room temperature, water and EA were added, and the organic phase was separated. It was dried over anhydrous sodium sulfate, concentrated, and further purified by silica gel column chromatography and preparative HPLC to give compound 26 as a pale yellow solid. LCMS [M+H] + =474,476.

[0256] Examples 27-31, 37-38, and 42-46: Synthesis and characterization of compounds 27-31, 37-38, and 42-46 According to general synthetic route I, TIFF2025530470000192.tif14170 is SM-1, Compound 27 was synthesized using TIFF2025530470000193.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =436.

[0257] According to general synthetic route I, TIFF2025530470000194.tif11170 is SM-1, Compound 28 was synthesized using TIFF2025530470000195.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =480. 1 H-NMR(400MHz,DMSO-d6)δ 11.27(s,1H),8.74-8.69(m,2H),7.70-7.65(m,1H),7.46-7.33(m,5H),7.02(d,J=6.0Hz,1H ),5.81-5.76(m,1H),4.98(t,J=7.2Hz,2H),4.70(dd,J=7.6,5.6Hz,2H),1.68-1.61(m,6H).

[0258] According to general synthetic route I, TIFF2025530470000196.tif11170 is SM-1, Using TIFF2025530470000197.tif10170 as Int-3 and dimethylphosphine oxide as SM-4, compound 29 was obtained. LCMS [M+H] + =496. 1 H-NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.74(d,J=6.0Hz,1H),8.68(dd,J=12.4,2.0Hz,1H),7.77-7.72(m,1H),7.66(d,J=8.4Hz,2H),7.55(dd,J=8.4,2.4Hz,1H),7. 42(d,J=8.4Hz,2H),7.03(d,J=6.0Hz,1H),5.80-5.74(m,1H),4.96(t,J=7.2Hz,2H),4.69(dd,J=7.6,5.6Hz,2H),1.70(s,3H),1.66(s,3H).

[0259] According to general synthetic route I, TIFF2025530470000198.tif12170 is SM-1, Compound 30 was synthesized using TIFF2025530470000199.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =438. 1 H-NMR(400MHz,DMSO-d6)δ 9.62(d,J=8.0Hz,1H),8.67-8.64(m,2H),7.65-7.59(m,1H),7.00-6.92(m,2H),5.77-5.71(m,1H), 4.99(t,J=7.2Hz,2H),4.70-4.68(m,2H),3.90-3.70(m,1H),2.08-2.02(m,6H),1.64-1.57(m,8H).

[0260] According to general synthetic route I, TIFF2025530470000200.tif14170 is SM-1, Compound 31 was synthesized using TIFF2025530470000201.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =454.

[0261] According to general synthetic route I, TIFF2025530470000202.tif11170 is SM-1, Compound 37 was synthesized using TIFF2025530470000203.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =454.

[0262] According to general synthetic route I, TIFF2025530470000204.tif11170 is SM-1, Compound 38 was synthesized using TIFF2025530470000205.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =428.

[0263] According to general synthetic route I, TIFF2025530470000206.tif14170 is SM-1, Compound 42 was synthesized using TIFF2025530470000207.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =432.

[0264] According to general synthetic route I, TIFF2025530470000208.tif18170 is SM-1, Compound 43 was synthesized using TIFF2025530470000209.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =432.

[0265] According to general synthetic route I, TIFF2025530470000210.tif16170 is SM-1, Compound 44 was synthesized using TIFF2025530470000211.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =374.

[0266] According to general synthetic route I, TIFF2025530470000212.tif12170 is SM-1, Compound 45 was synthesized using TIFF2025530470000213.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =398.

[0267] According to general synthetic route I, TIFF2025530470000214.tif11170 is SM-1, Compound 46 was synthesized using TIFF2025530470000215.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =412.

[0268] Example 32: Synthesis and characterization of compound 32 TIFF2025530470000216.tif29170

[0269] Intermediate Int-1 (1 eq), 3-hydroxymethylpyridone (1.2 eq), Pd(OAc)2 (0.1 eq), BINAP (0.1 eq), and cesium carbonate (2 eq) were added sequentially to DMF, purged with nitrogen, heated to 80 °C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, water and EA were added, filtered, and the filtrate was separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified by silica gel column chromatography to obtain intermediate 32-A as a yellow solid. LCMS [M+H] + =406.

[0270] TIFF2025530470000217.tif30170

[0271] Intermediate 32-A (1 eq), BocO (4 eq), and DMAP (0.5 eq) were dissolved in THF and reacted at 70°C for 16 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Intermediate 32-B (61% yield) as a yellow oil. LCMS [M+Na] + =628.

[0272] Compound 32 was synthesized according to general synthetic route I using 32-B as Int-5 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =437.

[0273] Example 33: Synthesis and characterization of compound 33 TIFF2025530470000218.tif28170

[0274] Intermediate Int-1 (1 eq), 4-(4-pyranyl)pyrazole (1.5 eq), CuI (0.2 eq), N,N'-dimethyltranscyclohexanediamine (0.2 eq), and potassium phosphate (2 eq) were added sequentially to DMSO, purged with nitrogen, heated to 80 °C, and stirred overnight. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, water and EA were added, filtered, and the filtrate was separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated, and further purified by silica gel column chromatography to obtain intermediate 33-A as a yellow solid. LCMS [M+H] + =433.

[0275] Compound 33 was synthesized according to general synthetic route I, using 33-A as Int-4 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =464.

[0276] Example 34: Synthesis and characterization of compound 34 According to general synthetic route I, TIFF2025530470000219.tif27170 is Int-2, Compound 34 was synthesized using TIFF2025530470000220.tif9170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =465. 1 H NMR (400 MHz, DMSO-d6) δ 8.66(s,1H),8.14(d,J=0.6Hz,1H),7.86(ddd,J=10.4,8.4,1.9Hz,1H),7.78(dd ,J=11.3,1.9Hz,1H),7.61(dd,J=8.4,2.1Hz,1H),7.58-7.52(m,2H),7.22(d,J= 8.5Hz,2H),4.15(ddd,J=11.5,7.4,4.0Hz,1H),3.79-3.69(m,2H),2.97(td,J=1 2.1,1.8Hz,2H),2.02-1.92(m,2H),1.69(s,3H),1.66(s,3H),1.64-1.58(m,2H).

[0277] Example 35: Synthesis and characterization of compound 35 According to general synthetic route I, TIFF2025530470000221.tif27170 is Int-2, Compound 35 was synthesized using TIFF2025530470000222.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =464. 1 H-NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.64(d,J=5.2Hz,1H),8.03(dd,J=11.6,2.0Hz,1H),7.82-7.77(m,1H),7.60-7.53(m,4H),7.22(d ,J=8.4Hz,2H),5.59-5.54(m,1H),4.82(t,J=7.2Hz,2H),4.61(dd,J=8.0,5.2Hz,2H),1.70(s,3H),1.67(s,3H).

[0278] Example 36: Synthesis and characterization of compound 36 According to general synthetic route I, TIFF2025530470000223.tif27170 is Int-2, Compound 36 was synthesized using TIFF2025530470000224.tif17170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =488.

[0279] Example 39: Synthesis and characterization of compound 39 TIFF2025530470000225.tif66170

[0280] Synthesis of intermediate 2: Starting material 1 (2.5 g, 8.4 mmol), starting material 2A (2.4 g, 12.5 mmol), Cu(OAc) (763 mg, 4.2 mmol), and DBU (2.56 g, 16.8 mmol) were added sequentially to DCM (45 mL) and stirred overnight at room temperature. The mixture was concentrated, 100 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography to give intermediate 2 (307 mg, 8.3% yield) as a brown solid. LCMS: m / z = 443, 445 (M+H). + ,ESI).

[0281] Compound 39 was obtained from intermediate 2 by the method of general synthetic route 1 in combination with the route shown in the diagram above. LCMS [M+H] + =465. 1 H-NMR(400MHz,DMSO-d6)δ 12.59(s,1H),9.01(dd,J=11.6,2.0Hz,1H),8.86(d,J=6.4Hz,1H),8.72(q,J=2.4Hz,1H),8.10(d,J=8.8Hz,2H),7.72(d,J=8.8 Hz,2H),7.12(d,J=6.0Hz,1H),5.87-5.81(m,1H),4.99(t,J=6.8Hz,2H),4.71(dd,J=8.0,5.2Hz,2H),1.77(s,3H),1.74(s,3H).

[0282] Example 40: Synthesis and characterization of compound 40 According to general synthetic route I, TIFF2025530470000226.tif27170 is Int-2, Compound 40 was synthesized using TIFF2025530470000227.tif14170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =430.

[0283] Example 41: Synthesis and characterization of compound 41 According to general synthetic route I, TIFF2025530470000228.tif27170 is Int-2, Compound 41 was synthesized using TIFF2025530470000229.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =437.

[0284] Example 47: Synthesis and characterization of compound 47 According to general synthetic route I, TIFF2025530470000230.tif22170 is Int-2, Compound 47 was synthesized using TIFF2025530470000231.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =450.

[0285] Example 48: Synthesis and characterization of compound 48 Compound 48 was synthesized using TIFF2025530470000232.tif15170 as the raw material, following the synthesis method for compound 32. LCMS [M+H] + =451.

[0286] Example 49: Synthesis and characterization of compound 49 TIFF2025530470000233.tif63170

[0287] Synthesis of intermediate A-2: Starting material A-1 (5.00 g, 20.24 mmol), Pd2(dba)3 (1.85 g, 2.02 mmol), XantPhos (2.34 g, 4.05 mmol), dimethylphosphine oxide (1.90 g, 24.29 mmol), and TEA (3.07 g, 30.36 mmol) were added sequentially to dioxane (75 mL), purged with nitrogen, and stirred overnight at room temperature. The mixture was concentrated, 100 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography using DCM-MeOH (0-10%) to give intermediate A-2 (1.70 g, 42.60% yield) as a yellow solid. LCMS: m / z = 198.0 (M + H) + ,ESI)

[0288] Synthesis of intermediate A-3: Compound A-2 (500 mg, 2.54 mmol) was dissolved in DMSO (5 mL), m-trifluoromethylbenzylamine (883 mg, 5.07 mmol) was added, and the mixture was heated to 100 °C and reacted for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The organic phase was further purified on a silica gel column using DCM:MeOH (0-10%) (1% TEA) to give intermediate A-3 (630 mg, 70.51% yield) as a yellow solid. LCMS: m / z = 353.1 (M+H) + ,ESI)

[0289] Synthesis of intermediate A-4: Sodium carbonate (746 mg, 7.04 mmol) was added to a suspension of compound A-3 (630 mg, 1.76 mmol) and hydroxylamine hydrochloride (611 mg, 8.80 mmol) in ethanol (20 mL). After the addition was complete, the mixture was heated to 80°C and reacted for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, evaporated to dryness, extracted with EA, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate A-4 (500 mg, 71.14% yield) as a yellow solid. This was used directly in the next reaction without further purification. LCMS: m / z = 386.1 (M + H +,ESI)

[0290] Synthesis of intermediate A-5: Acetyl chloride (118 mg, 1.50 mmol) was added to a solution of compound A-4 (400 mg, 1.14 mmol) in pyridine (5 mL) under ice bath conditions. After the addition was complete, the mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature. An appropriate amount of water was added to quench the reaction. Direct purification was performed on a C18 column using water:acetonitrile (0-50%) (0.1% formic acid) to obtain A-5 (230 mg, 50.87% yield) as a white solid. LCMS: m / z = 410.1 (M+H + ,ESI)

[0291] Synthesis of compound 49: Compound A-5 (200 mg, 0.44 mmol) was dissolved in hydrazine hydrate (15 mL, 5.07 mmol). After the addition was complete, the mixture was heated to 70 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and then directly purified on a C18 column using water:acetonitrile (0-50%) (0.1% formic acid) to give compound 49 (30 mg, 16.54% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.36(dd,J=11.9,1.9Hz,1H),7.75(d,J=1.8Hz,1H),7.67-7.57(m,5H),6.84(dd, J=8.7,2.3Hz,1H),4.75(d,J=6.0Hz,2H),2.70(s,3H),1.59(s,3H),1.56(s,3H). LCMS:m / z=410.1(M+H + ,ESI).

[0292] Example 50: Synthesis and characterization of compound 50 TIFF2025530470000234.tif74170

[0293] Synthesis of intermediate A-2: Starting material A-1 (2.00 g, 6.65 mmol), Pd2(dba)3 (304 mg, 0.33 mmol), XantPhos (385 mg, 0.66 mmol), dimethylphosphine oxide (623 mg, 7.98 mmol), and TEA (1.01 g, 9.97 mmol) were added sequentially to dioxane (50 mL), purged with nitrogen, and stirred overnight at room temperature. The mixture was concentrated, 100 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography using DCM-MeOH (0-10%) to give intermediate A-2 (150 mg, 8.99% yield) as a red solid. LCMS: m / z = 251.0 (M+H) + ,ESI).

[0294] Synthesis of intermediate A-3: Compound A-2 (120 mg, 0.48 mmol) was dissolved in DMSO (3 mL), p-trifluoromethylbenzylamine (167 mg, 0.96 mmol) was added, and the mixture was heated to 120 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and further purified on a silica gel column using DCM:MeOH (0-10%) (1% TEA) to give intermediate A-3 (100 mg, 51.50% yield) as a yellow solid. LCMS: m / z = 406.0 (M+H) + ,ESI).

[0295] Synthesis of compound 50: A solution of compounds A-3 (70 mg, 0.17 mmol) and A-4 (43 mg, 0.17 mmol) in dioxane (0.8 mL) and water (0.2 mL) was added to Pd(dppf)Cl 2(The reaction mixture was concentrated, 50 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography (C18) using water:acetonitrile (0-50%) (0.1% formic acid) to give compound 50 (10 mg, 12.91% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.20(s,1H),7.87(s,1H),7.68(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.42(dd,J=11.5,1.9Hz,1H),7.33(ddd,J=10.8,8.3,2.0Hz,1H),6. 48(dd,J=8.4,2.4Hz,1H),6.22(t,J=6.2Hz,1H),5.66(t,J=7.1Hz,1H),5.02-4.94(m,4H),4.50(d,J=6.0Hz,2H),1.55(s,3H),1.52(s,3H). LCMS:m / z=450.1(M+H + ,ESI).

[0296] Example 51: Synthesis and characterization of compound 51 TIFF2025530470000235.tif26170

[0297] Synthesis of intermediate 2 Compound 1 (200 mg, 1.36 mmol) was dissolved in anhydrous THF (5 mL), and NaH (163 mg, 4.08 mmol) was added at 0 °C. The mixture was stirred at this temperature for 0.5 h. Compound 1A (433 mg, 2.04 mmol) was dissolved in anhydrous THF (5 mL) and added to the reaction mixture. The mixture was further stirred at room temperature for 16 h. After monitoring the reaction completion by LCMS, 50 mL of aqueous ammonium chloride solution was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a silica gel column (PE:EA = 1:1) to give P065 (100 mg, purity 90%, yield 28.62%) as a yellow solid. LCMS [M+1] + =230.9 / 232.8.

[0298] Synthesis of intermediate 3 Intermediate 3 (300 mg, 1.30 mmol), compound 2A (363 mg, 1.43 mmol), Pd(dppf)Cl2 (94 mg, 0.130 mmol), and anhydrous potassium acetate (382 mg, 3.89 mmol) were added sequentially to 1,4-dioxane (25 mL), purged with nitrogen, heated to 90 °C, and stirred for 12 hours. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, and 100 mL of water and 150 mL of EA were added. The filtrate was separated to obtain the organic phase, which was dried over anhydrous sodium sulfate. The organic phase was concentrated and further purified on a silica gel column (PE:EA = 1:1) to obtain intermediate 7 (205 mg, 90% purity, 51.09% yield) as a yellow solid. LCMS [M+1] + =279.30.

[0299] Synthesis of compound 51 Intermediate 3 (85 mg, 0.305 mmol), compound 4 (100 mg, 0.255 mmol), Pd(dppf)Cl2 (19 mg, 0.250 mmol), and cesium carbonate (250 mg, 0.760 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), purged with nitrogen, heated to 90 °C, and stirred for 12 hours. After monitoring the reaction completion by LCMS, the mixture was cooled to room temperature, and 50 mL of water and 75 mL of EA were added. The filtrate was separated to obtain the organic phase, which was dried over anhydrous sodium sulfate. The organic phase was concentrated and further purified on a silica gel column (DCM:MeOH = 10:1) to obtain compound 51 (15.2 mg, purity 96.47%, yield 12.37%) as a yellow solid. LCMS [M+H + ]=463.9. 1 H-NMR(400MHz,DMSO-d6)δ 8.35(s,1H),8.09(s,1H),7.86(dd,J=12,2.0Hz,1H),7.76(s,1H),7.62-7.57(m,1H),7.46-7.42(m,3H),6.93(d, J=8.8Hz,2H),4.42-4.34(m,1H),3.94-3.91(m,2H),3.48-3.41(m,2H),1.92-1.82(m,4H),1.68(d,J=13.6Hz,6H).

[0300] Example 52: Synthesis and characterization of compound 52 TIFF2025530470000236.tif29170

[0301] Synthesis of intermediate 2 Xantphos (2.88 g, 4.99 mmol, 0.05 eq), Pd2(dba)3 (4.56 g, 4.99 mmol, 0.05 eq), and TEA (15.13 g, 149.55 mmol, 21.02 mL, 1.5 eq) were added to THF (200 mL) and the mixture was purged with nitrogen three times. After stirring at 25 °C for 30 min, a solution of compound 1 (30 g, 99.70 mmol, 1 eq) and compound 1A (8 g, 102.50 mmol, 1.03 eq) in THF (100 mL) was added and stirred for an additional 3 h. LCMS showed the reaction was complete, with the product being formed. After filtration and concentration, the crude product was purified on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to give Intermediate 2 (15.60 g, 59.04 mmol, 59.21% yield, 95% purity) as a yellow oil. LCMS [M+H] + =250.8 TIFF2025530470000237.tif34170

[0302] Synthesis of intermediate 3 2 (1 g, 3.98 mmol, 1 eq) was dissolved in DMSO (5 mL), compound 2A (1.40 g, 7.97 mmol, 2 eq) was added, and the mixture was stirred at 130 °C for 16 h. LCMS showed that the product was produced. The mixture was diluted with water, extracted with EA, washed with 1N aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column (acetonitrile / pure water) to give intermediate 3 (360.00 mg, 797.68 μmol, 20.02% yield, 90.00% purity) as a yellow oil. LCMS [M+H] + =405.7

[0303] Synthesis of compound 52 Intermediate 3A (330.76 mg, 1.77 mmol, 2 eq), Intermediate 3 (360 mg, 886.31 μmol, 1 eq), KI (176.55 mg, 1.06 mmol, 1.2 eq), Mn (194.77 mg, 3.55 mmol, 4 eq), 4-ethylpyridine (94.97 mg, 886.31 μmol, 100.82 μL, 1 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (118.94 mg, 443.16 μmol, 0.5 eq), nickel(II) bromide ethylene glycol The methyl ether complex (136.77 mg, 443.16 μmol, 0.5 eq) was dissolved in DMAc (10 mL), and the mixture was stirred at 90 °C for 16 h. The reaction was monitored for completion by LCMS. Water (100 mL) was added, extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 52 (85.00 mg, 174.84 μmol, 19.73% yield, 98.74% purity) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 9.96(t,J=6.0Hz,1H),8.71-8.64(m,2H),7.75(s,1H),7.68-7.53(m,4H),6.96(d,J=6.0Hz,1H),6 .79-6.74(m,1H),5.76-5.68(m,1H),4.96(t,J=7.2Hz,2H),4.74-4.66(m,4H),1.65-1.59(m,6H). LCMS[M+H] + =477.8.

[0304] Example 53: Synthesis and characterization of compound 53 According to general synthetic route I, TIFF2025530470000238.tif22170 is Int-2, Compound 53 was synthesized using TIFF2025530470000239.tif15170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =487.

[0305] Example 54: Synthesis and characterization of compound 54 According to the synthetic route of compound 17, Using TIFF2025530470000240.tif20170 as the raw material, TIFF2025530470000241.tif11170 Compound 54 was synthesized. LCMS [M+H] + =491.

[0306] Example 55: Synthesis and characterization of compound 55 According to general synthetic route I, TIFF2025530470000242.tif22170 is Int-2, Compound 55 was synthesized using TIFF2025530470000243.tif9170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =479.

[0307] Example 56: Synthesis and characterization of compound 56 According to general synthetic route I, TIFF2025530470000244.tif22170 is Int-2, Compound 56 was synthesized using TIFF2025530470000245.tif14170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =487.

[0308] Example 57: Synthesis and characterization of compound 57 According to general synthetic route I, TIFF2025530470000246.tif27170 is Int-2, Compound 57 was synthesized using TIFF2025530470000247.tif10170 as Int-3 and dimethylphosphine oxide as SM-4. LCMS [M+H] + =468.

[0309] Example 58: Synthesis and characterization of compound 58 According to the synthetic route of compound 33, TIFF2025530470000248.tif27170 Compound 58 was synthesized. LCMS [M+H] + =478.

[0310] Example 59: Synthesis and characterization of compound 59 According to the synthetic route of compound 32, TIFF2025530470000249.tif46170 Compound 59 was synthesized. LCMS [M+H] + =465.

[0311] Example 60: Synthesis and characterization of compound 60 TIFF2025530470000250.tif59170

[0312] Synthesis of intermediate 2 Under nitrogen protection, XantPhos (39.40 mg, 0.068 mmol, 0.2 eq), Pd2(dba)3 (31.18 mg, 0.034 mmol, 0.1 eq), and TEA (103.36 mg, 1.02 mmol, 3 eq) were dissolved in anhydrous DMF (5 mL) and the mixture was stirred at room temperature for 30 min. Next, a solution of Int4 (200 mg, 0.34 mmol, 1 eq) from Example 3 and Al (122.19 mg, 0.51 mmol, 1.5 eq) in DMF (5 mL) was added, and the mixture was further reacted at 110 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 40 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting crude product was purified using a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to obtain Intermediate 2 (150 mg, 0.21 mmol, purity 86%, yield 61.8%) as a yellow solid. LCMS [M+H] + =698.8.

[0313] Synthesis of intermediate 3 Intermediate 2 (200 mg, 0.29 mmol, 1 eq) was dissolved in ultra-dry dichloromethane (10 mL) and cooled to 0 °C under nitrogen protection. mCPBA (98.79 mg, 0.57 mmol, 2 eq) was added, and then the ice bath was removed and the mixture was allowed to warm to room temperature (25 °C). The reaction was monitored by LCMS and stirred until completion. The mixture was filtered and slurried with DCM to give a mixture of Intermediate 3 and 3A (180 mg, 0.25 mmol, 79% purity, 86% yield) as a yellow solid. Intermediate 3: LCMS [M+H] + =714.7, Intermediate 3A: LCMS[M+H] + =730.7.

[0314] Synthesis of intermediate 4 Compound A2 (40.55 mg, 0.55 mmol, 2 eq) was dissolved in ultra-dry THF (10 mL), purged with nitrogen three times, and NaH (43.79 mg, 1.09 mmol, 60% purity, 4 eq) was added in an ice bath, and the mixture was stirred for 0.5 h. Next, intermediate 3 (196 mg, 0.27 mmol, 1 eq) was added. The reaction was continued for another 2 h at 0 °C, and the reaction completion was monitored by LCMS. The reaction was quenched by adding 10 mL of ice water, extracted with EA (40 mL x 3), and the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give intermediate 4 (180 mg, crude product) as a yellow solid. LCMS [M+H] + =740.8.

[0315] Synthesis of intermediate 5 Intermediate 4 (600 mg, 810.04 μmol, 1 eq), Zn (529.69 mg, 8.10 mmol, 10 eq), and NH4Cl (649.95 mg, 12.15 mmol, 15 eq) were dissolved in EtOH (25 mL) and HO (5 mL) and stirred at 70 °C for 16 h under nitrogen protection. The reaction was monitored for completion by LCMS, filtered, water (50 mL) and EA (50 mL) were added, the filtrate was separated, the aqueous phase was extracted with EA, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give Intermediate 5 (500 mg, crude) as a yellow solid. LCMS [M+H] + =724.8.

[0316] Synthesis of intermediate 6 Intermediate 5 (200 mg, 270.73 μmol, 1 eq) and CAN (861.23 mg, 1.62 mmol, 6 eq) were dissolved in MeCN (10 mL) and stirred at 0° C. for 3 h under nitrogen protection. The reaction was monitored for completion by LCMS. Water (20 mL) and EA (20 mL) were added, the filtrate was separated, the aqueous phase was extracted with EA (20 mL×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give Intermediate 6 (150 mg, crude product) as a yellow solid. LCMS [M+H] + =605.3.

[0317] Synthesis of compound 60 Intermediate 6 (50 mg, 80.83 μmol) was dissolved in 30% TFA in DCM (20 mL) and stirred at 25° C. for 3 h under nitrogen protection. The reaction was monitored for completion by LCMS. The mixture was diluted with EA, cooled to 0° C., adjusted to alkaline pH with aqueous sodium bicarbonate, extracted with EA, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 60 (2.00 mg, 3.67 μmol, 4.54% yield, 95.09% purity) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 11.39(s,1H),8.76(d,J=5.6Hz,1H),8.71-8.66(m,1H),7.76-7.68(m,3H),7.58(dd,J=8.4,2.4Hz,1H),7.48(d,J=8.8Hz,2H),7.04(d,J=6.0Hz) ,1H),5.80-5.74(m,1H),4.96(t,J=7.2Hz,2H),4.71-4.67(m,2H),3.68 -3.57(m,1H),3.16-2.93(m,3H),2.16-1.97(m,2H),1.86-1.72(m,2H). LCMS[M+H] + =504.9.

[0318] Example 61: Synthesis and characterization of compound 61 TIFF2025530470000251.tif77170

[0319] Synthesis of intermediate 3 Compound 1 (3 g, 10.07 mmol), compound 2 (1.91 g, 10.07 mmol), DBU (3.07 g, 20.14 mmol), and anhydrous copper acetate (915 mg, 5.03 mmol) were added to dichloromethane (20 mL), and the mixture was further filtered and purged with oxygen three times. The mixture was stirred at 25 °C for 16 h. After filtration, concentration, and column purification (pure PE), the product intermediate 3 (600 mg, 1.36 mmol, 13.5% yield) was obtained as a brown liquid.

[0320] Synthesis of intermediate 5 Compound 3 (3 g, 6.79 mmol), compound 4 (1.18 g, 7.13 mmol), and nickel bromide (149 mg, 678.71 μmol) were added to a single-neck flask, purged with nitrogen three times, and reacted at 160 °C for 6 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified using a column chromatography to obtain the product, intermediate 5 (1.5 g, 3.32 mmol, 48.89% yield), as a brown solid. LCMS [M+1]+ = 452.0.

[0321] Synthesis of intermediate 6 Compound 5 (1 g, 2.21 mmol) and phosphorus oxychloride (679 mg, 4.42 mmol) were added to a three-necked flask, and the mixture was purged with nitrogen three times. Phosphorus pentachloride (1.15 g, 5.53 mmol) was added in an ice-water bath, and the mixture was reacted at 100° C. for 16 hours. After concentration, the crude product, compound 6 (900 mg), was obtained as a brown solid, which was used directly in the next reaction.

[0322] Synthesis of intermediate 7 Compound 6 (900 mg) and tetrahydrofuran (10 mL) were added to a three-necked flask, and the mixture was purged with nitrogen three times. Vinyl magnesium bromide (1.36 g, 10.39 mmol) was added dropwise at -78°C, and the reaction was carried out at -78°C for 2 hours. The reaction was quenched by adding ice water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain the product, intermediate 7 (400 mg), as a brown solid. LCMS [M+H] + =415.7 / 417.7.

[0323] Synthesis of compound 61 Intermediate Int-3 (269.02 mg, 1.44 mmol, 2 eq), intermediate 7 (300 mg, 720.86 μmol, 1 eq), 4-ethylpyridine (77.24 mg, 720.86 μmol, 82.00 μL, 1 eq), Mn (237.62 mg, 4.33 mmol, 6 eq), KI (143.59 mg, 865.03 μmol, 1.2 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (580.43 mg, 2.16 mmol, 3 eq), and nickel(II) bromide ethylene glycol dimethyl ether complex (667.41 mg, 2.16 mmol, 3 eq) were dissolved in DMAc (20 mL) and stirred at 100 °C for 16 h under nitrogen protection. The reaction was monitored for completion by LCMS, water (100 mL) was added, extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column (HO (0.1% NHOH) / ACN) to give compound 61 (7.20 mg, 14.77 μmol, 2.05% yield, 98.47% purity) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ 11.44(s,1H),8.75(d,J=6.0Hz,1H),8.62(d,J=12.8Hz,1H),7.70-7.56(m,4H),7.48(d,J=7.7Hz,2H),7.04(d,J=6.0Hz,1H) ,6.78-6.64(m,2H),6.31(d,J=12.6Hz,1H),6.22-6.12(m,3H),5.75-5.70(m,1H),4.95(t,J=6.6Hz,2H),4.70-4.60(m,2H). LCMS[M+H] + =487.5.

[0324] Example 62: Synthesis and characterization of compound 62 TIFF2025530470000252.tif34170

[0325] Synthesis of intermediate 2 Intermediate 20-Int3 (300 mg, 1.20 mmol, 1 eq) of compound 20 was dissolved in DMSO (5 mL), compound 1A (342.11 mg, 2.39 mmol, 2 eq) was added, and the mixture was stirred at 130° C. for 16 hours. LCMS showed that the product was produced. Dilution with water, extraction with EA, washing with 1N aqueous hydrochloric acid and saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave intermediate 2 (120.00 mg, crude product) as a yellow solid. LCMS [M+H] + =373.7.

[0326] Synthesis of compound 62 Intermediate Int-3 (149.61 mg, 801.80 μmol, 2 eq), Intermediate 2 (150 mg, 400.90 μmol, 1 eq), KI (79.86 mg, 481.08 μmol, 1.2 eq), Mn (44.05 mg, 801.80 μmol, 2 eq), 4-ethylpyridine (42.96 mg, 400.90 μmol, 1 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (53.80 mg, 200.45 μmol, 0.5 eq), nickel(II) bromide ethylene glycol Cholesterol dimethyl ether complex (61.86 mg, 200.45 μmol, 0.5 eq) was dissolved in DMAc (10 mL), the mixture was stirred at 90 °C for 16 h, and the reaction completion was monitored by LCMS. Water (100 mL) was added, extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 62 (60.00 mg, 134.71 μmol, 33.60% yield, 100% purity) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 9.92(t,J=6.0Hz,1H),8.71-8.65(m,2H),7.58-7.53(m,1H),7.15-7.05(m,3H),6.99-6.92(m,1H),6.73(dd,J =8.7,2.4Hz,1H),5.77-5.71(m,1H),4.97(t,J=7.2Hz,2H),4.71-4.66(m,4H),1.60(dd,J=28.2,15.2Hz,6H). LCMS[M+H] + =445.8.

[0327] Example 63: Synthesis and characterization of compound 63 TIFF2025530470000253.tif40170

[0328] Synthesis of intermediate 2 Intermediate 20-Int3 (240 mg, 956.05 μmol, 1 eq) of compound 20 and compound 1A (1.04 g, 6.21 mmol, 6.5 eq) were dissolved in DMAc (4 mL). The mixture was stirred in a microwave oven at 160 °C for 4 h. The reaction was monitored for completion by LCMS. The mixture was then cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to give intermediate 2 (70 mg, 0.18 mmol, 18.75% yield, 84.56% purity) as a black oil. LCMS [M+H] + =398.0.

[0329] Synthesis of compound 63 Intermediate 2 (80 mg, 200.91 μmol, 1 eq) was dissolved in DMF (3 mL), Pd(dppf)Cl (29.16 mg, 40.18 μmol, 0.2 eq) was added, and the mixture was stirred in a microwave at 160 °C for 4 h. LCMS showed that the product was produced and the reaction was complete. Water (30 mL) was added, and the mixture was extracted with EA (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 63 (9.50 mg, 23.73 μmol, 11.81% yield, 99.77% purity) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ 9.05(d,J=8.4,Hz,1H),7.79-7.66(m,3H),7.38-7.32(m,1H),6.85-6.72(m,1H),3.90-3.88(m,1H),3.76-3 .68(m,3H),2.43-2.09(m,2H),1.99-1.86(m,2H),1.76-1.61(m,4H),1.59-1.55(m,6H),1.49-1.26(m,1H). LCMS[M+H] + =400.2.

[0330] Example 64: Synthesis and characterization of compound 64 TIFF2025530470000254.tif27170

[0331] Synthesis of intermediate 2 Compound 1 (10 g, 33.57 mmol, 1 eq), compound 1A (9.56 g, 50.35 mmol, 1.5 eq), anhydrous copper acetate (13.40 g, 67.13 mmol, 2 eq), and DBU (21.69 g, 167.83 mmol, 29.23 mL, 5 eq) were dissolved in DCM (250 mL) and stirred at room temperature under an oxygen atmosphere for 48 h. LCMS indicated that starting material remained and the reaction did not continue for extended periods. The mixture was filtered, concentrated, and purified on a silica gel column (eluent: PE / EA = 10 / 1) to give intermediate 2 (7 g, 15.84 mmol, 82% purity, 47.18% yield) as a yellow solid. LCMS: The product had no molecular weight.

[0332] Synthesis of intermediate 3 Under nitrogen protection, XantPhos (1.31 g, 2.26 mmol, 0.05 eq), Pd(dba) (1.24 g, 1.36 mmol, 0.03 eq), and TEA (9.16 g, 90.50 mmol, 12.58 mL, 2 eq) were dissolved in anhydrous THF (300 mL) and the mixture was stirred at room temperature for 30 min. Next, a solution of Intermediate 2 (20 g, 45.25 mmol, 1 eq) and compound 2A (3.88 g, 49.77 mmol, 1.1 eq) in THF (100 mL) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored for completion by LCMS, filtered, and concentrated under reduced pressure. The resulting crude product was purified on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to obtain intermediate 3 (13 g, 33.15 mmol, purity 88%, yield 73.26%) as a yellow solid. LCMS [M+H] + =392.0.

[0333] Synthesis of compound 64 Intermediate 3A (9.38 g, 45.08 mmol, 1.7 eq), Intermediate 3 (10.4 g, 26.52 mmol, 1 eq), 4-ethylpyridine (2.84 g, 26.52 mmol, 3.02 mL, 1 eq), Zn (10.41 g, 159.12 mmol, 6 eq), KI (5.28 g, 31.82 mmol, 1.2 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (7.12 g, 26.52 mmol, 1 eq), and nickel(II) bromide ethylene glycol dimethyl ether complex (8.18 g, 26.52 mmol, 1 eq) were dissolved in DMAc (150 mL) and stirred at 90 °C for 16 h under nitrogen protection. The reaction was monitored for completion by LCMS, water (300 mL) was added, extracted with EA (300 mL × 3), and the organic phase was washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase column (HO (0.1% NHOH) / ACN) to give compound 64 (2.00 g, 5.08 mmol, 19.17% yield, 98.46% purity) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.04(d,J=12.0Hz,1H),7.81(t,J=24.8Hz,2H),7.61-7.52(m,4H),7.31(d,J=8.4Hz,2H),3.75(s,3H),1.67(d,J=13.2Hz,6H). LCMS[M+H] + =394.0.

[0334] Example 65: Synthesis and characterization of compound 65 According to the synthetic route of compound 64, TIFF2025530470000255.tif15170 Compound 65 was synthesized. LCMS [M+H] + =458.

[0335] Example 66: Synthesis and characterization of compound 66 TIFF2025530470000256.tif33170

[0336] Synthesis of intermediate 3 Under nitrogen protection, XantPhos (340.35 mg, 588.22 μmol, 0.1 eq), Pd(dba) (538.64 mg, 588.22 μmol, 0.1 eq), and TEA (1.19 g, 11.76 mmol, 1.64 mL, 2 eq) were dissolved in anhydrous THF (300 mL) and the mixture was stirred at room temperature for 30 min. Next, a solution of intermediate 64-Int2 (2.6 g, 5.88 mmol, 1 eq) and compound 2A (624.12 mg, 5.88 mmol, 1 eq) in THF (100 mL) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored for completion by LCMS, filtered, and concentrated under reduced pressure. The resulting crude product was purified on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to give Intermediate 3 (1.60 g, 3.43 mmol, 58.26% yield, 90.00% purity) as a yellow solid. LCMS [M+H] + =419.8.

[0337] Synthesis of compound 66 Intermediate Int-3 (301.96 mg, 1.62 mmol, 1.7 eq), Intermediate 3 (400 mg, 951.92 μmol, 1 eq), 4-ethylpyridine (102.00 mg, 951.92 μmol, 108.28 μL, 1 eq), Mn (313.78 mg, 5.71 mmol, 6 eq), KI (189.62 mg, 1.14 mmol, 1.2 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (766.49 mg, 2.86 mmol, 3 eq), and nickel(II) bromide ethylene glycol dimethyl ether complex (881.35 mg, 2.86 mmol, 3 eq) were dissolved in DMAc (20 mL) and stirred at 100 °C for 16 h under nitrogen protection. The reaction was monitored for completion by LCMS, water (100 mL) was added, extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column (HO (0.1% NHOH) / ACN) to give compound 66 (50.00 mg, 99.71 μmol, 10.47% yield, 98.47% purity) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ 11.32(s,1H),8.75(d,J=5.6Hz,1H),8.65(dd,J=10.8,2.4Hz,1H),7.70-7.65(m,3H),7.56(dd,J=8.4,2.4Hz,1H),7.47(d,J=8.4Hz,2H) ),7.03(d,J=5.6Hz,1H),5.79-5.74(m,1H),4.95(t,J=7.2Hz,2H),4.69(dd,J=7.6,4.8Hz,2H),2.04-1.82(m,4H),1.033-0.953(m,6H). LCMS[M+H] + =492.1.

[0338] Example 67: Synthesis and characterization of compound 67 TIFF2025530470000257.tif25170

[0339] Synthesis of intermediate 2 Compound 1 (2 g, 6.71 mmol, 1 eq), compound 1A (2.07 g, 10.07 mmol, 1.5 eq), anhydrous copper acetate (2.44 g, 13.43 mmol, 2 eq), and DIEA (4.34 g, 33.57 mmol, 5.85 mL, 5 eq) were dissolved in DCM (50 mL) and stirred at room temperature under an oxygen atmosphere for 48 h. LCMS indicated that starting material remained and the reaction did not continue for extended periods. Filtration, concentration, and purification on a silica gel column (eluent: PE / EA = 10 / 1) afforded intermediate 2 (1.3 g, 2.84 mmol, 42.32% yield, 83% purity) as a yellow solid. LCMS: The product had no molecular weight.

[0340] Synthesis of intermediate 3 Under nitrogen protection, XantPhos (12.63 mg, 21.83 μmol, 0.05 eq), Pd2(dba)3 (12.00 mg, 13.10 μmol, 0.03 eq), and TEA (88.37 mg, 0.87 mmol, 2 eq) were dissolved in anhydrous THF (15 mL) and the mixture was stirred at room temperature for 30 min. Next, a solution of intermediate 2 (0.2 g, 436.67 μmol, 1 eq) and compound 2A (36.52 mg, 480.34 μmol, 1.1 eq) in THF (5 mL) was added, and the mixture was reacted at 25 °C for an additional 16 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (3 x 50 mL), and the organic phase was washed with saturated brine (2 x 70 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting crude product was purified on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to obtain Intermediate 3 (130.00 mg, 318.51 μmol, 72.94% yield, 92.67% purity) as a yellow solid. LCMS [M+H] + =407.7.

[0341] Synthesis of compound 67 Intermediate Int-3 (233.16 mg, 1.25 mmol, 1.7 eq), Intermediate 3 (300 mg, 735.02 μmol, 1 eq), KI (146.42 mg, 882.03 μmol, 1.2 eq), Mn (161.53 mg, 2.94 mmol, 4 eq), 4-ethylpyridine (78.76 mg, 735.02 μmol, 83.61 μL, 1 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (59.18 mg, 220.51 μmol, 0.3 eq), nickel(II) bromide ethyl ester Glycol dimethyl ether complex (68.05 mg, 220.51 μmol, 0.3 eq) was dissolved in DMAc (10 mL), and the mixture was stirred at 90° C. for 16 h. The reaction was monitored for completion by LCMS. Water (100 mL) was added, extracted with EA (100 mL×3), and the organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 67 (63.00 mg, 131.42 μmol, 17.88% yield, 100% purity) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 11.27(s,1H),8.75-8.68(m,2H),7.74-7.69(m,1H),7.49(t,J=8.4Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),7.35-7.33(m,1H) ),7.27(s,1H),7.06-7.01(m,2H),5.81-5.75(m,1H),4.97(t,J=7.2Hz,2H),4.71-4.66(m,2H),1.70(s,3H),1.63(s,3H). LCMS[M+H] + =480.1.

[0342] Example 68: Synthesis and characterization of compound 68 TIFF2025530470000258.tif66170

[0343] Step 1: Synthesis of intermediate 3 Compound 1 (10 g, 33.57 mmol), compound 2 (6.38 g, 33.57 mmol), DIPEA (21.69 g, 167.83 mmol), and anhydrous copper acetate (12.19 g, 67.13 mmol) were added to dichloromethane (50 mL), and the mixture was further filtered with 4A molecular sieves, purged with oxygen three times, and stirred at 25 °C for 16 h. After filtration, concentration, and column purification (pure PE), the product intermediate 3 (4 g, 9.05 mmol, 26.95% yield) was obtained as a brown liquid.

[0344] Step 2: Synthesis of intermediate 5 Intermediate 3 (44.7 g, 101.13 mmol), compound 4 (18.48 g, 111.24 mmol), palladium acetate (2.27 g, 10.11 mmol), and anhydrous 1,4-dioxane (500 mL) were added to a single-neck flask, purged with nitrogen three times, and reacted at 90 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain the product, intermediate 5 (22 g, 3.32 mmol, 48.10% yield), as a brown solid.

[0345] Step 3: Synthesis of intermediate 6 Intermediate 5 (20.9 g, 46.22 mmol), bis-pinacol borate (23.47 g, 92.44 mmol), Pd(dppf)Cl (3.39 g, 4.62 mmol), and potassium acetate (13.61 g, 138.65 mmol) were added to 1,4-dioxane (100 mL), purged with nitrogen three times, and reacted at 100 °C for 16 h. After filtration, the organic phase was concentrated to give the crude product, Intermediate 6 (22 g), as a brown liquid, which was used directly in the next step.

[0346] Step 4: Synthesis of intermediate 7 Intermediate 6 (23 g), 4-iodo-1-methylimidazole (14.37 g, 69.1 mmol), Pd(dppf)Cl (3.38 g, 4.61 mmol), and cesium carbonate (45.03 g, 138.2 mmol) were added to 1,4-dioxane (100 mL) and water (20 mL), and the mixture was purged with nitrogen three times and reacted at 100 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain the product, Intermediate 7 (10 g, 22.06 mmol, 47.86% yield), as a brown liquid.

[0347] Step 5: Synthesis of intermediate 8 Intermediate 7 (10 g, 22.06 mmol) was added to phosphorus oxychloride (16.91 g, 110.28 mmol), and the mixture was purged with nitrogen three times. Phosphorus pentachloride (11.48 g, 55.14 mmol) was added at 0° C., and the mixture was reacted at 100° C. for 16 hours. The reaction mixture was concentrated to obtain the crude product, Intermediate 8 (9 g), as a brown solid compound, which was used directly in the next step.

[0348] Step 6: Synthesis of Compound 68 Intermediate 8 (9.5 g, 21.88 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a three-neck flask, purged with nitrogen three times, and vinylmagnesium bromide (109.4 mL, 1 M THF solution, 109.4 mmol) was added at -78 °C. The reaction was allowed to proceed at -78 °C for 2 hours. Ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified on a silica gel column to give the product as a brown solid. This was further purified on a reverse-phase column (0.5% aqueous ammonia / acetonitrile system) to give compound 68 (500 mg, 1.2 mmol, purity 95%, yield 5.48%) as a pale yellow powder. 1HNMR(400MHz,DMSO-d6)δ 10.75(s,1H),7.92(dd,J=12.4,1.6Hz,1H),7.84(s,1H),7.75(d,J=0.8Hz,1H),7.59(d,J=8.6Hz,2H),7.52(dd,J=8.2,2.8Hz,1H),7. 45-7.40(m,1H),7.29(d,J=8.6Hz,2H),6.77-6.62(m,2H),6.25(dd,J=12.6,2.2Hz,1H),6.17(s,1H),6.14-6.06(m,2H),3.72(s,3H). LCMS[M-1] - =416.1.

[0349] Example 69: Synthesis and characterization of compound 69 TIFF2025530470000259.tif35170

[0350] Synthesis of compound 69 Compound 1 (282.60 mg, 1.73 mmol, 1.7 eq), intermediate 64-Int3 (400 mg, 1.02 mmol, 1 eq), Mn (336.23 mg, 6.12 mmol, 6 eq), KI (115.42 mg, 694.63 μmol, 1.2 eq), 4-ethylpyridine (109.29 mg, 1.02 mmol, 116.02 μL, 1 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (821.32 mg, 3.06 mmol, 3 eq), and nickel(II) bromide. Ethylene glycol dimethyl ether complex (944.39 mg, 3.06 mmol, 3 eq) was dissolved in DMAc (20 mL), the mixture was stirred at 90 °C for 16 h, and the reaction completion was monitored by LCMS. Water (100 mL) was added, extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 69 (15.00 mg, 36.81 μmol, 3.61% yield, 97.70% purity) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ 9.59(s,1H),8.25(dd,J=11.6,2.0Hz,1H),7.84-7.79(m,1H),7.71(d,J=8.4Hz,2H),7. 61(dd,J=8.4,2.0Hz,1H),7.50(d,J=8.0Hz,2H),2.63(s,3H),1.69(s,3H),1.66(s,3H). LCMS[M+H] + =396.0.

[0351] Example 70: Synthesis and characterization of compound 70 TIFF2025530470000260.tif31170

[0352] Synthesis of intermediate 3 Compound 1 (2.5 g, 18.25 mmol, 1.5 eq) and compound 2 (1.79 g, 12.17 mmol, 1 eq) were dissolved in DMF (50 mL), cesium carbonate (7.93 g, 24.34 mmol, 2 eq) was added, and the mixture was stirred at 130 °C for 16 h under nitrogen protection. The reaction was monitored for completion by LCMS. Water (100 mL) was added, and the mixture was extracted with EA (100 mL × 3). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (eluent: EA) to give intermediate 3 (2.00 g, 8.87 mmol, 72.86% yield, 90% purity) as a yellow solid. LCMS [M+H] + =202.8.

[0353] Synthesis of compound 70 Intermediate 3 (200 mg, 984.06 μmol, 1.7 eq), intermediate 64-Int3 of compound 64 (227 mg, 578.86 μmol, 1 eq), KI (115.42 mg, 694.63 μmol, 1.2 eq), Mn (191.01 mg, 3.47 mmol, 6 eq), 4-ethylpyridine (62.09 mg, 578.86 μmol, 65.91 μL, 1 eq), 4,4'-di- tert-Butyl-2,2'-bipyridine (466.56 mg, 1.74 mmol, 3 eq) and nickel(II) bromide ethylene glycol dimethyl ether complex (536.48 mg, 1.74 mmol, 3 eq) were dissolved in DMAc (20 mL). The mixture was stirred at 90 °C for 16 h. After completion of the reaction was monitored by LCMS, water (100 mL) was added and extracted with EA (100 mL × 3). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 70 (8.70 mg, 19.95 μmol, 3.45% yield, 99.84% purity) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 10.71(s,1H),8.26(d,J=1.2Hz,1H),8.12-8.06(m,2H),7.61-7.50(m,4H),7.30(d,J=8.8Hz,2 H),5.59-5.52(m,1H),4.98(t,J=7.4Hz,2H),4.84(t,J=6.6Hz,2H),1.69(s,3H),1.66(s,3H). LCMS[M+H] + =436.0.

[0354] Example 71: Synthesis and characterization of compound 71 TIFF2025530470000261.tif53170

[0355] Synthesis of intermediate A-3: Raw materials A-1 (6.00 g, 20.14 mmol), A-2 (5.74 g, 30.21 mmol), copper acetate (7.32 g, 40.28 mmol), DIEA (7.81 g, 60.42 mmol), and an appropriate amount of 4A molecular sieves were added sequentially to DCM (120 mL). The atmosphere was purged with oxygen, and the mixture was stirred at room temperature under an oxygen atmosphere for 48 h. The insoluble material was removed by suction to obtain a filtrate, which was then concentrated. Purification was then carried out by flash column chromatography using PE-EA (0-10%) to obtain intermediate A-3 (3.10 g, 34.82% yield) as a yellow solid. No liquid was produced. 1 HNMR(400MHz,Chloroform-d)δ 7.87(d,J=2.0Hz,1H),7.55(d,J=8.5Hz,2H),7.50(dd,J=8.6,2.0Hz,1H),7.14(d,J=8.4Hz,2H),7.10(d,J=8.6Hz,1H),6.18(s,1H).

[0356] Synthesis of intermediate A-4: Starting material A-3 (3.00 g, 6.79 mmol), Pd2(dba)3 (622 mg, 0.68 mmol), XantPhos (785 mg, 1.36 mmol), dimethylphosphine oxide (689 mg, 8.82 mmol), and TEA (1.03 g, 10.18 mmol) were added sequentially to 1,4-dioxane (60 mL), purged with nitrogen, and stirred overnight at room temperature. The mixture was concentrated, 100 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography using DCM-MeOH (0-5%) to give intermediate A-4 (2.30 g, 86.41% yield) as a yellow solid. LCMS: m / z = 392.0 (M+H) + ,ESI).

[0357] Synthesis of intermediate B-2: 0 oUnder C conditions, NaH (247 mg, 6.17 mmol, 60% purity) was added to a solution of oxetan-3-ol (396 mg, 5.35 mmol) in DMF (5 mL). After 1 h, the solution was added dropwise to a solution of B-1 (1.00 g, 4.12 mmol) in DMF (5 mL) at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was quenched with ice water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified by flash column chromatography using PE-EA (0-20%) to give intermediate B-2 (730 mg, 75.11% yield) as a colorless viscous oil. LCMS: m / z = 237.1 (M+H) + ,ESI).

[0358] Synthesis of intermediate B-3: Compound B-2 (300 mg, 1.27 mmol) in dioxane (5 mL) was dissolved in Pd(dppf)Cl 2( To the mixture were added B2(Pin)2 (355 mg, 1.40 mmol), potassium acetate (374 mg, 3.81 mmol), and B2(Pin)2 (355 mg, 1.40 mmol) in that order. After the addition was complete, the mixture was purged with nitrogen, heated to 100 °C, and reacted for 3 h. After concentration, the boronic acid (256 mg, 100% yield, theoretical) was obtained as a black solid, which was used directly in the next step without further purification. LCMS: m / z = 202.0 (M+H + ,ESI). LCMS showed the molecular weight of boric acid.

[0359] Synthesis of compound 71 (TJJS-24): A solution of compound A-4 (330 mg, 0.84 mmol) and B-3 (220 mg, 1.09 mmol) in dioxane (1 mL) and water (0.25 mL) was added to Pd(dppf)Cl 2(The mixture was then added with cesium carbonate (548 mg, 1.68 mmol) and 62 mg (0.084 mmol). After the addition was complete, the mixture was purged with nitrogen, heated to 100°C, and reacted for 3 hours. The mixture was concentrated, 50 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by flash column chromatography (C18) using water:acetonitrile (0-50%) (0.1% formic acid) to give compound 71 (TJJS-24) (80 mg, 20.30% yield) as a white solid. LCMS: m / z = 469 (M+H + ,ESI). 1 H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),7.97(dd,J=11.8,1.9Hz,1H),7.66(ddd,J=10.4,8.3,1.9Hz, 1H),7.57(d,J=8.5Hz,2H),7.49(dd,J=8.4,2.4Hz,1H),7.45(s,1H),7.20 (d,J=8.5Hz,2H),5.71(ddd,J=6.1,4.7,1.3Hz,1H),4.85(ddd,J=7.3,6.1 ,1.1Hz,2H),4.65(ddd,J=7.8,4.8,1.0Hz,2H),1.68(s,3H),1.65(s,3H).

[0360] Example 72: Synthesis and characterization of compound 72 TIFF2025530470000262.tif26170

[0361] Synthesis of intermediate A-3: A mixture of starting materials A-1 (6.00 g, 20.14 mmol), A-2 (5.74 g, 30.21 mmol), copper acetate (7.32 g, 40.28 mmol), DIEA (7.81 g, 60.42 mmol), and an appropriate amount of 4A molecular sieves was added to DCM (120 mL), purged with oxygen, and stirred at room temperature for 48 h under an oxygen atmosphere. The insoluble material was removed by suction to obtain a filtrate, which was then concentrated. Further purification by flash column chromatography using PE-EA (0-10%) afforded intermediate A-3 (3.10 g, 34.82% yield) as a yellow solid. No liquid was produced. 1HNMR(400MHz,Chloroform-d)δ 7.87(d,J=2.0Hz,1H),7.55(d,J=8.5Hz,2H),7.50(dd,J=8.6,2.0Hz,1H),7.14(d,J=8.4Hz,2H),7.10(d,J=8.6Hz,1H),6.18(s,1H).

[0362] Synthesis of intermediate A-4: Starting material A-3 (3.00 g, 6.79 mmol), Pd2(dba)3 (622 mg, 0.68 mmol), XantPhos (785 mg, 1.36 mmol), dimethylphosphine oxide (689 mg, 8.82 mmol), and TEA (1.03 g, 10.18 mmol) were added sequentially to 1,4-dioxane (60 mL), purged with nitrogen, and stirred overnight at room temperature. The mixture was concentrated, 100 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by flash column chromatography using DCM-MeOH (0-5%) to give intermediate A-4 (2.30 g, 86.41% yield) as a yellow solid. LCMS: m / z = 392.0 (M + H) + ,ESI).

[0363] Synthesis of compound 72 (TJJS-26): DMAc (2 mL) was added to a mixture of compound A-4 (150 mg, 0.38 mmol), compound A-5 (93 mg, 0.57 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (31 mg, 0.11 mmol), 4-ethylpyridine (41 mg, 0.38 mmol), potassium iodide (63 mg, 0.38 mmol), manganese powder (63 mg, 1.15 mmol), and ethylene glycol dimethyl ether (NiBr) (45 mg, 0.11 mmol). After the addition was complete, the atmosphere was purged with nitrogen, and the mixture was heated to 90°C and reacted overnight. After concentration, 30 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated and further purified on a 1 mm thin-layer chromatography silica gel plate using DCM-MeOH (10%) to give compound 72 (TJJS-26) (10 mg, yield 6.63%) as a white solid. LCMS: m / z = 393 (MH + ,ESI).1 H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),8.73(d,J=0.7Hz,1H),8.48(dd,J=11.9,1.9Hz,1H),7.66(dd,J=9.4,3.2Hz,3H ),7.57(dd,J=8.5,2.5Hz,1H),7.43(d,J=8.4Hz,2H),4.00(s,3H),1.67(s,4H),1.63(s,4H).

[0364] Example 73: Synthesis and characterization of compound 73 According to the synthesis route of compound 64, the starting material, compound 1, TIFF2025530470000263.tif24170 Compound 73 was synthesized. LCMS [M+H] + =396.

[0365] Example 74: Synthesis and characterization of compound 74 TIFF2025530470000264.tif94170

[0366] Step 1: Synthesis of intermediate A-2 Compound A-1 (1.204g, 4mmol), Pd2 (dba) 3( Xantphos (110 mg, 0.12 mmol) and Xantphos (120 mg, 0.2 mmol) were dissolved in 10 mL of tetrahydrofuran, and dimethylphosphine oxide (343 mg, 4.4 mmol) and triethylamine (808 mg, 8 mmol) were added under nitrogen protection and stirred at room temperature for 16 hours. The solids were removed by filtration through Celite, concentrated, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the product, Intermediate A-2 (650 mg, 65.3% yield), as a brown liquid.

[0367] Step 2: Synthesis of intermediate A-3 Intermediate A-2 (310 mg, 1.0 mmol) and compound A-4 (260 mg, 1.2 mmol) were dissolved in 3 mL of dimethyl sulfoxide, and potassium hydroxide (112 mg, 2 mmol) was added. oThe mixture was heated to 90°C and reacted for 16 hours. The mixture was quenched by adding 10 ml of water and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, added to a single-neck flask, purged with nitrogen three times, and reacted at 90°C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified using a column (dichloromethane:methanol = 15:1) to obtain the product A-3 (200 mg, yield 44.4%).

[0368] Step 3: Synthesis of compound 74 Intermediate A-3 (630 mg, 1.6 mmol), compound A-5 (417 mg, 2.24 mmol), Mn (308 mg, 5.6 mmol), 4-ethylpyridine (150 mg, 1.4 mmol), potassium iodide (279 mg, 1.68 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (113 mg, 0.42 mmol), and nickel(II) bromide ethylene glycol dimethyl ether complex (129 mg, 0.42 mmol) were dissolved in N,N-dimethylacetamide (15 mL) and heated under nitrogen protection for 90 minutes. o The mixture was heated to C and reacted for 16 hours. The solid was removed by filtration through Celite, the solvent was dried by rotary evaporation, EA (10 mL) was added, silica gel was added, the sample was mixed, and purified by column chromatography (dichloromethane:methanol = 12:1) to give the product 74 (30 mg, yield 4.1%). LCMS [M+1] + =522. 1 HNMR(400MHz,d6-DMSO)δ 11.31(s,1H),8.74(d,J=5.9Hz,1H),8.67(dd,J=12.3,1.9Hz,1H),7.86-7.80(m,2H),7.76(ddd,J=10.3,8.6,1.9Hz,1H),7.60(dd,J=8.5 ,2.3Hz,1H),7.42(d,J=8.9Hz,2H),7.03(d,J=5.9Hz,1H),5.75(m,1H),4.95(m,2H),4.68(dd,J=7.9,5.3Hz,2H),1.68(d,J=13.3Hz,6H).

[0369] Example 75: Synthesis and characterization of compound 75 Using the intermediate A-3 in the synthesis step of Example 74 as a raw material, the reaction conditions of Step 3 in the synthesis step of Example 64 were adopted, TIFF2025530470000265.tif9170 was subjected to a reductive coupling reaction to give compound 75. LCMS [M+1] + =452.

[0370] Example 76: Synthesis and characterization of compound 76 TIFF2025530470000266.tif34170

[0371] Intermediate 3 in the synthesis step of Example 66, i.e., A-1 in the above diagram (250 mg, 594.95 μmol, 1 eq) was dissolved in DMF (5 mL), 1-methyl-4-tri-n-butylstannylimidazole (264.98 mg, 713.94 μmol, 1.2 eq) and Pd(dppf)Cl (43.17 mg, 59.50 μmol, 0.1 eq) were added, and the reaction system was stirred at 130 °C for 16 hours under nitrogen protection. LCMS showed that the product was produced and the reaction was complete. Water (30 mL) was added, extracted with EA (20 mL × 3), and the organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (acetonitrile / aqueous ammonia) to give 76 (40.00 mg, 94.92 μmol, 15.95% yield, 100% purity) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.00-7.94(m,1H),7.86-7.76(m,2H),7.60(d,J=8.4Hz,2H),7.55-7. 44(m,2H),7.31(d,J=8.4Hz,2H),3.74(s,3H),2.08-1.82(m,4H),1.10-0.80(m,6H). LC-MS[M+H] + =422.1.

[0372] Test Example 1: Testing the effect of compounds on the melting point curve of recombinant TEAD1 / 2 / 3 / 4 proteins The ability of compounds to increase the melting point of purified recombinant TEAD1 / 2 / 3 / 4 proteins was tested using a thermal shift assay. The melting point shift (ΔTm) in °C was calculated to evaluate the binding strength of the compounds to the proteins and their selectivity in binding to the four TEAD subtypes. A larger ΔTm value indicates a stronger protein stabilization ability and stronger binding ability of the compound. Depending on the ΔTm value, the binding ability of the compounds to TEAD proteins was classified into four levels: ++++, +++, ++, and +.

[0373] [Table 1] TIFF2025530470000268.tif252170

[0374] a TEAD1 protein sequence: 194-411 (Uniprot ID: P28347) b TEAD2 protein sequence: 218-447 (Uniprot ID: Q15562) c TEAD3 protein sequence: 218-435 (Uniprot ID: Q99594) d TEAD4 protein sequence: 217-434 (Uniprot ID: Q15561)

[0375] Protein Melting Point Curve Test Method: According to the following system, 10 μL of the protein melting curve assay system (10 μM TEAD protein, 50 μM test compound, SYPRO® orange (S5692, Sigma)) was placed in a 384-well fluorescent quantitative PCR plate and reacted in the dark at 4°C for 20 minutes. On-board reaction: ABI QuantStudio Dx fluorescent quantitative PCR instrument; procedure: The plate was heated from 25°C to 80°C at a rate of 0.05°C / second, and the fluorescent channel signal of the corresponding wavelength of SYPRO® orange was read every second.

[0376] The above results indicate that the compounds in Table 1 have different binding abilities to TEAD family proteins, and some compounds such as 6, 7, 8, 21, 22, 45, 61, 64, 68, 72, 73, 75, and 76 have good binding abilities to each subtype of TEAD family proteins and therefore have strong physiological activities.

[0377] Test Example 2. High-resolution mass spectrometry to detect irreversible binding of covalent compounds to recombinant TEAD protein Covalent inhibitors bind irreversibly to target proteins, thereby exerting a prolonged pharmacological effect. Compounds 61 and 68 are covalent inhibitors, possessing chemical groups that can irreversibly bind to the conserved cysteine ​​residue in the palmitoyl pocket of TEAD proteins. However, most reported TEAD inhibitors, such as VT103, are noncovalent. Therefore, compounds 61 and 68 bind irreversibly to TEAD proteins, resulting in a more prolonged pharmacological effect. To demonstrate the covalent binding properties, 10 equivalents of compound 68 were incubated with 1 equivalent of TEAD1 or TEAD4 protein at 37°C for 1 hour, and changes in protein molecular weight were detected by liquid chromatography-high-resolution mass spectrometry. As shown in Figures 1 and 2, the results showed that the molecular weight of TEAD proteins after incubation increased by the molecular weight value of compound 68, demonstrating its ability to irreversibly bind and label TEAD proteins.

[0378] The above results demonstrated that compound 68 can covalently bind to TEAD proteins and is superior to non-covalent inhibitors such as VT103.

[0379] Test Example 3: In vitro liver microsome stability test of compounds Testosterone was selected as the positive reference compound. The specific method is as follows.

[0380] 0.1 M K3PO4 (pH 7.4) buffer and 3x NADPH stock solution (6 mM, 5 mg / mL) were prepared and preheated in a 37°C water bath.

[0381] Preparation of spiking solutions of test and control compounds: 5 μL of compound stock solution (10 mM) was added to 95 μL of acetonitrile.

[0382] Preparation of 1.5 μM spiking solution in microsomes (0.75 mg / mL): 1.5 μL of spiking solution and 18.75 μL of liver microsome solution (20 mg / mL) were added to 479.75 μL of K3PO4 buffer. 30 μL of the spiking solution in microsomes was added to a multi-well plate and incubated at 37°C for 5 minutes. 15 μL of NADPH stock solution was added to each well to initiate the reaction, which was then timed. 150 μL of IS-containing acetonitrile solution was added at 0, 5, 15, 30, 45, and 60 minutes to terminate the reaction. The reaction was shaken for 10 minutes and then centrifuged at 6000 rpm for 15 minutes. 80 μL of the supernatant was collected from each well for LC / MS detection. 1 / 2 Some of the test results are shown in Figures 3a-3h.

[0383] As shown in Figures 3a-3h, compounds 1, 8, 28, 64, and 68 exhibited good metabolic stability in vitro in mouse and human liver microsome environments, and compound 8 exhibited good metabolic stability in rat and dog liver microsome environments.

[0384] Mouse, rat, dog, and human liver microsomes used in the experiments were purchased from Xenotech.

[0385] Test Example 4: Mouse plasma pharmacokinetics test of compound In this example, pharmacokinetic experiments were carried out in mice using various compounds. The specific procedures are as follows:

[0386] Animal information: CD-1 mice, male, approximately 20 g, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0387] Animal feeding status: Animals were not fasted prior to dosing and had free access to water.

[0388] Compound preparation method: Oral administration (Group G1) was prepared with 0.5% CMC-Na, and intravenous injection (Group G2) was prepared with 5% DMSO + 30% PEG400 + 65% water for injection.

[0389] Oral administration (Group G1): The compound was administered orally to the experimental animals at a dose of 10 mg / kg (10 mL / kg) (n=9). Intravenous administration (Group G2): The compound was administered intravenously to the experimental animals at a dose of 1 mg / kg (10 mL / kg) (n=9).

[0390] Sampling time points for Group G1: 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, for a total of eight time points. Of these, samples were collected from animals G1M01 to G1M03 at 10 minutes, 1 hour, and 6 hours, for a total of three time points; samples from animals G1M04 to G1M06 at 30 minutes, 2 hours, and 8 hours, for a total of three time points; and samples from animals G1M07 to G1M09 at 4 hours and 24 hours, for a total of two time points.

[0391] Sampling time points for Group G2: 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. It is recommended that samples be collected from animals G2M01 to G2M03 at three time points: 5 minutes, 1 hour, and 6 hours; from animals G2M04 to G2M06 at three time points: 10 minutes, 2 hours, and 8 hours; and from animals G2M07 to G2M09 at three time points: 30 minutes, 4 hours, and 24 hours.

[0392] Sample collection: On the day of the experiment, approximately 0.1 mL of whole blood samples were collected at each set time point and placed into EDTA-K2 anticoagulated tubes.

[0393] Sample processing: Whole blood samples were centrifuged at 12,000 rpm at 4°C for 5 minutes within 30 minutes of collection, and the upper plasma sample was collected into a sample tube. The plasma sample was frozen in a refrigerator at -10 to -30°C within 30 minutes and transferred to a refrigerator at -60 to -90°C within 24 hours.

[0394] Sample assay and data processing: LC / MS / MS detection, fitting and pharmacokinetic parameter calculation were performed using WinNonlin. The results are shown in Figures 4a-4c and Table 2.

[0395] [Table 2]

[0396] As shown in Figures 4a-4e and Table 2, compounds 17 and 64 exhibited favorable pharmacokinetic properties in mice.

[0397] The existing TEAD palmitoyl pocket inhibitor, VT103, was also tested in a similar manner, and the PK parameters of VT103 in mice were evaluated using intravenous T 1 / 2 = 13.2 hours, Vss = 4.5 L / kg, Cl = 4.7 mL / min / kg, oral bioavailability = 75%, C of 7 mg / kg orally max = 896ng / mL, plasma drug concentration after 24 hours C 24h =340ng / mL.

[0398] The inventors believe that VT103 (Tang et al., 2021, Mol Cancer Ther. 20(6):986-998) is too lipophilic, and pharmacokinetic studies in mice have shown that its apparent volume of distribution is too large (V SSTwenty-four hours after oral administration of 7 mg / kg in a 24-hour IVF system (4.5 L / kg), the blood drug concentration remained high at 340 ng / ml (828 nM). This suggests that VT103 accumulates in tissues after absorption into the blood and is slowly excreted, leading to a tendency for accumulation and high toxicity. In contrast, the compounds of the present invention have moderate plasma clearance rates and tissue distribution, which reduces the tendency for tissue accumulation and significantly improve oral bioavailability.

[0399] Test Example 5: Compound permeability test in Caco2 cells TIFF2025530470000270.tif50170

[0400] After resuscitation, Caco-2 cells were transferred to a standard culture dish and cultured in a high-sugar DMEM medium (containing 10% FBS) at 37°C in a 5% CO2 incubator. When the cells covered 80% to 95% of the bottom of the dish, they were digested with trypsin containing 0.25% EDTA, dispersed into a single-cell suspension, and the cell concentration was measured using a cell counter. The cell suspension was then diluted with fresh medium to a concentration of 2 to 2.5 x 10 cells. 5 The medium was adjusted to 1 / mL and seeded into 12-well plates with transwell polycarbonate membranes. Fresh medium was replaced every 2 days for the first 2 weeks, and fresh medium was replaced once a day for the last week. Fully differentiated monolayers were obtained after 19–21 days of continuous culture. TIFF2025530470000271.tif78170

[0401] The medium on the AP and BL sides of the transwell chamber was aspirated, and blank HBSS solution preheated to 37°C was added. The mixture was then equilibrated at 37°C for 20 minutes. The HBSS solution was then aspirated, and preheated drug solution was added to either the AP or BL side, while blank HBSS solution was added to the opposite side (BL or AP). The mixture was then incubated at 37°C for 120 minutes with constant shaking. All samples from the AP and BL sides were collected and stored at -60 to -90°C before use in the study.

[0402] [Table 3]

[0403] The above test results suggest that compounds 8 and 17 have high intestinal permeability and are completely absorbed from the intestinal tract.

[0404] Test Example 6: Testing the binding ability of compounds to the central pocket of recombinant TEAD protein (competitive thiol binding assay, CPM assay) Test compounds were gradient-diluted into 5 μL of buffer (25 mM HEPES, 150 mM NaCl, pH 6.5), followed by the addition of 5 μL of a freshly prepared 0.45 μM recombinant TEAD protein solution and incubation at room temperature for 10 min. Next, 5 μL of a 0.45 μM CPM [7-diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin] solution was added, resulting in a final volume of 15 μL containing 150 nM recombinant TEAD protein and 150 nM CPM. The plate was shaken at room temperature for 1 h, and the fluorescence intensity was measured (Ex / Em: 380 / 470 nm). If the test compound does not bind to the central pocket of the TEAD protein, the cysteine ​​thiol group in the central pocket reacts with CPM to generate a fluorescent conjugated group (see Figure 5). If the test compound can bind to the central pocket of the TEAD protein, the pocket will be occupied, and the cysteine ​​thiol group in the pocket will not be able to react with CPM, resulting in no fluorescent absorbing group. The test results for several compounds are shown in the following table.

[0405] [Table 4] TIFF2025530470000274.tif247170TIFF2025530470000275.tif49170

[0406] The above test results demonstrate that the compounds of the present invention have a high binding ability to the central pocket of TEAD protein, and that the binding ability of the compounds of the present invention is stronger than that of the reported positive control compound VT103.

[0407] Test Example 7: Plasma pharmacokinetics test of compound in SD rats Animal information: SD rats, male, n=6, approximately 180-200 g, purchased from SPF (Beijing) Biotechnology Co., Ltd.

[0408] Animal feeding status: Animals were fasted for at least 12 hours before dosing and resumed eating 4 hours after dosing. Animals had free access to water throughout the experiment.

[0409] Administration: The compounds were orally administered to experimental animals (n=3) at a dose of 10 mg / kg in 0.5% CMC-Na as a vehicle, and the compounds were intravenously injected to experimental animals (n=3) at a dose of 1 mg / kg in DMSO:PEG400:saline = 5:30:65 as a vehicle, prepared extemporaneously.

[0410] Sample collection: Approximately 0.25 mL of whole blood was collected at each time point, anticoagulated with EDTA-K2, placed on ice immediately after collection, and centrifuged at 2000 g for 5 minutes at 4°C within 0.5 hours of collection. All plasma was collected and placed into labeled EP tubes, which were then placed on ice. The plasma samples were then frozen and stored in a refrigerator at -60 to -90°C within 0.5 hours.

[0411] Sample processing: Whole blood samples were centrifuged at 2000 g for 5 minutes at 4°C within 30 minutes of collection to separate the plasma, and the upper plasma sample was collected in a sample tube.

[0412] Sample assay and data processing: An LC-MS / MS method was used to detect the concentration of unchanged drug in plasma samples at each time point. WinNonlin was used for fitting and calculation of pharmacokinetic parameters. The results are shown in Figures 6a and 6b and Table 5.

[0413] [Table 5]

[0414] As shown in Figures 6a and 6b and Table 5, compound 17 exhibited good pharmacokinetic properties in SD rats.

[0415] It will be understood by those skilled in the art that the above-described embodiments are specific examples for implementing the present invention, and that in actual applications, various changes in form and details may be made without departing from the spirit and scope of the present invention.

Claims

1. A compound having the structure shown in general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, where: Z is -CH ２ -, -NH(CH ２ )n-, -O(CH ２ )n-, -S-, -SO-, -SO ２ -, where each n is independently an integer from 0 to 3; R １ is C １－６ Alkyl, C ２－６ alkenyl, at least one hydrogen is R １－１ C substituted with １－６ alkyl, at least one hydrogen is R １－１ C substituted with ２－６ alkenyl; R ２ is C １－６ Alkyl, C ２－６ alkenyl, at least one hydrogen is R １－１ C substituted with １－６ alkyl, at least one hydrogen is R １－１ C substituted with ２－６ alkenyl; Or, R １ and R ２ are bonded to form a 4- to 6-membered ring, or at least one hydrogen atom is bonded to R １－１ wherein each R １－１ are independently amino, hydroxy, hydroxy-substituted C １－６ alkyl, 5- or 6-membered monocyclic heteroaryl; Ring A is Here, X １ is CH or N, X ２ is CH or N; Ring B is a 5- to 10-membered heteroaryl, at least one hydrogen atom of which is a 5- to 10-membered heteroaryl substituted with, a 5- to 10-membered heteroaryl ketone group, a 5- to 10-membered heteroaryl ketone group substituted with where L is absent or -CH ２ -, -NH-, -O-, -CH ２ O-, -S-, -SO-, or -SO ２ - and; Each R ３ is independently absent or hydroxyl, C １－６ alkyl, at least one hydrogen is R ３－１ C substituted with １－６ Alkyl, amino, at least one hydrogen is R ３－１ amino substituted with 3- to 6-membered heterocycloalkyl, at least one hydrogen atom is R ３－１ 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom, ３－１ is a 5- or 6-membered monocyclic heteroaryl substituted with Each R ３－１ are independently hydroxy, C in which at least one hydrogen is replaced by hydroxy １－４ Alkyl, C １－４ alkoxy, halogen; Ring C is phenyl, and at least one hydrogen is R ４ phenyl substituted with 3- to 7-membered monocycloalkyl, at least one hydrogen atom is R ４ 3-7 membered monocycloalkyl substituted with C ５－１２ Bridged bicycloalkyl, at least one hydrogen is R ４ C substituted with ５－１２ Bridged bicycloalkyl, C １０－２０ Bridged tricycloalkyl, at least one hydrogen is R ４ C substituted with １０－２０ Bridged tricycloalkyl, 8- to 10-membered benzocycloalkyl, at least one hydrogen atom is R ４ 8-10 membered benzocycloalkyl substituted with Each R ４ is independently C １－４ Alkyl, C in which at least one hydrogen is replaced by halogen １－４ Alkyl, halogen, 3- to 6-membered cycloalkyl, C １－４ Alkoxy, C in which at least one hydrogen is replaced by halogen １－４ Alkoxy, C １－４ Alkylthiol, C in which at least one hydrogen is replaced by halogen １－４ A compound having the structure shown in general formula (I), which is an alkylthiol, halogen-substituted mercaptan, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

2. Each R １ are independently methyl, ethyl, or １－１ methyl substituted with at least one hydrogen atom; １－１ ethyl, vinyl substituted with, Each R ２ are independently methyl, ethyl, or １－１ methyl substituted with at least one hydrogen atom; １－１ ethyl, vinyl substituted with, where R １－１ is amino, hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl; Or, R １ and R ２ are bonded to each other to form a 4- to 6-membered ring, or R １ and R ２ are bonded to each other so that at least one hydrogen atom is R １－１ wherein each R １－１ is independently amino, hydroxy, methyl substituted with hydroxy, ethyl substituted with hydroxy, or a 5- or 6-membered nitrogen-containing monocyclic heteroaryl; and / or ring A is and / or Ring B is a 5-membered nitrogen-containing monocyclic heteroaryl, a 6-membered nitrogen-containing monocyclic heteroaryl, or a 5-membered nitrogen-containing monocyclic heteroaryl, 5-membered nitrogen-containing monocyclic heteroaryl substituted with a 6-membered nitrogen-containing monocyclic heteroaryl substituted with a 8- to 10-membered nitrogen-containing fused ring heteroaryl substituted with, a 5-membered nitrogen-containing monocyclic heteroaryl ketone group, a 6-membered nitrogen-containing monocyclic heteroaryl ketone group, a 5-membered nitrogen-containing monocyclic heteroaryl ketone group substituted with at least one hydrogen atom a 6-membered nitrogen-containing monocyclic heteroaryl ketone group substituted with and / or Ring C is phenyl, at least one hydrogen is R ４ phenyl substituted with 4- to 6-membered monocycloalkyl, at least one hydrogen atom is R ４ 4-6 membered monocycloalkyl substituted with C ５－８ Bridged bicycloalkyl, at least one hydrogen is R ４ C substituted with ５－１２ Bridged bicycloalkyl, C １０－２０ Bridged tricycloalkyl, at least one hydrogen is R ４ C substituted with １０－２０ Bridged tricycloalkyl, 8- to 10-membered benzocycloalkyl, at least one hydrogen atom is R ４ 2. The compound of claim 1, wherein the benzocycloalkyl group is an 8- to 10-membered benzocycloalkyl substituted with:

3. In the ring B, the 5- or 6-membered nitrogen-containing monocyclic heteroaryl is and and / or, in the ring B, the at least one hydrogen atom is A 5-membered nitrogen-containing monocyclic heteroaryl substituted with and and / or, in the ring B, the at least one hydrogen atom is A 6-membered nitrogen-containing monocyclic heteroaryl substituted with and and / or, in said ring B, said 8-10 membered nitrogen-containing monocyclic heteroaryl is and and / or, in the ring B, the at least one hydrogen atom is 8-10 membered nitrogen-containing monocyclic heteroaryl substituted with and and / or, in the ring B, the 6-membered nitrogen-containing monocyclic heteroaryl ketone group is and and / or said at least one hydrogen A 6-membered nitrogen-containing monocyclic heteroaryl ketone group substituted with 3. The compound of claim 2, wherein:

4. In the ring C, the at least one hydrogen atom is R ４ Phenyl substituted with and and / or in said ring C, said 4-6 membered monocycloalkyl is cycloalkyl, cyclopentyl, or cyclobutyl; and / or, in the ring C, the one hydrogen atom is R ４ 4-6 membered monocycloalkyl substituted with and and / or in the ring C, the C ５－８ Bridged bicycloalkyl is bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl; and / or, in the ring C, the at least one hydrogen atom is R ４ C substituted with ５－１２ Bridged bicycloalkyl is one hydrogen atom of R ４ or bicyclo[1.1.1]pentyl substituted with R ４ bicyclo[2.2.2]octyl substituted with and / or in the ring C, the C １０－２０ The bridged tricycloalkyl is adamantyl; and / or, in the ring C, the at least one hydrogen atom is R ４ C substituted with １０－２０ Bridged tricycloalkyl is one hydrogen atom of R ４ adamantyl substituted with and / or in said ring C, said 8-10 membered benzocycloalkyl is benzocyclopentyl, benzocyclobutyl or benzocyclohexyl; and / or, in the ring C, the at least one hydrogen atom is R ４ The 8- to 10-membered benzocycloalkyl substituted with at least one hydrogen atom is R ４ benzocyclopentyl substituted with at least one hydrogen atom; ４ or a benzocyclobutyl substituted with at least one hydrogen atom in which R ４ 3. The compound of claim 2, wherein the compound is benzocyclohexyl substituted with .

5. Each R ３ are independently hydroxyl, cyano, C １－４ alkyl, at least one hydrogen is R ３－１ C substituted with １－４ Alkyl, amino, at least one hydrogen is R ３－１ amino substituted with 3- to 6-membered azacycloalkyl, 3- to 6-membered oxacycloalkyl, at least one hydrogen atom of which is R ３－１ 3-6 membered azacycloalkyl substituted with at least one hydrogen atom, ３－１ a 3- to 6-membered oxacycloalkyl substituted with a 6-membered nitrogen-containing monocyclic heteroaryl; ３－１ is a 6-membered nitrogen-containing monocyclic heteroaryl substituted with and / or each R ３－１ are independently hydroxy, methyl in which at least one hydrogen is replaced by hydroxy, ethyl in which at least one hydrogen is replaced by hydroxy, n-propyl in which at least one hydrogen is replaced by hydroxy, isopropyl in which at least one hydrogen is replaced by hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine or chlorine; and / or each R ４ are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methyl in which at least one hydrogen is substituted with fluorine, ethyl in which at least one hydrogen is substituted with fluorine, n-propyl in which at least one hydrogen is substituted with fluorine, isopropyl in which at least one hydrogen is substituted with fluorine, fluorine, chlorine, bromine, iodine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, hexafluoroethoxy, methyl mercapto, ethyl mercapto, n-propyl mercapto, isopropyl mercapto, methyl mercapto in which at least one hydrogen is substituted with fluorine, ethyl mercapto in which at least one hydrogen is substituted with fluorine, or a halogen-substituted mercaptan.

6. Each R ３ are independently hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or a group in which at least one hydrogen is R ３－１ methyl substituted with at least one hydrogen atom; ３－１ ethyl substituted with at least one hydrogen atom; ３－１ n-propyl substituted with at least one hydrogen atom; ３－１ isopropyl, amino, at least one hydrogen atom of which is substituted with R ３－１ amino substituted with 2. The compound of claim 1, wherein:

7. The compound according to any one of claims 1 to 6, characterized in that the compound is selected from any one of the following compounds:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament or pharmaceutical composition for use in one or more applications selected from the following: (i) binds to TEAD; preferably binds to the palmitoyl pocket of TEAD; (ii) inhibition of TEAD transcript levels; (iii) inhibition / blocking of YAP-TEAD binding; (iv) regulation of the Hippo signaling pathway; (v) treating diseases associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway; and / or (vi) The manufacture of a medicament for treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or a disorder of the Hippo signaling pathway.

10. Administering a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof to a subject; or Administering the pharmaceutical composition of claim 8 to a subject; A method for treating a disease associated with increased TEAD transcription levels and / or dysregulation of YAP phosphorylation and / or disorders of the Hippo signaling pathway, comprising:

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