Small molecule inhibitors targeting ubiquitin-specific protease 1 (USP1) and uses thereof

Abstract

The present application provides small molecules targeting ubiquitin specific protease 1 (USP1), and / or pharmaceutical compositions comprising the same, which can be used to treat diseases or disorders caused by diseases or disorders associated with ubiquitin specific protease 1 (USP1), such as, but not limited to, cancer, and other diseases or conditions associated with DNA damage, etc., particularly cancer associated with BRCA1 or BRCA2 mutations.

Description

Technical Field

[0001] This application relates to the fields of chemical drug synthesis and pharmacological applications, specifically to inhibitors of ubiquitin-specific protease 1 (USP1) for the treatment of diseases or disorders associated with USP1. In particular, this application relates to compounds and compositions thereof that inhibit USP1, methods for treating USP1-related diseases or conditions, and methods for their chemical synthesis. Background Technology

[0002] Ubiquitin is a small protein composed of 76 amino acids. Ubiquitination refers to the process by which ubiquitin proteins specifically modify target proteins under the action of a series of specialized enzymes. Normally, polyubiquitinated proteins are degraded by the proteasome, while monoubiquitinated proteins participate in the regulation of cellular pathways. Ubiquitination is a reversible process called deubiquitination, involving a series of deubiquitinating enzymes (DUBs). These enzymes regulate various cellular processes by removing ubiquitin from target proteins.

[0003] DUBs are encoded by approximately 100 human genes and are divided into 7 families (USP, UCH, SENP, JAMM, OUT, MJD, MINDY). The largest family is the ubiquitin-specific protease (USP), which has more than 50 protein members.

[0004] USP1 is a deubiquitinase in the ubiquitin-specific protease (USP1) family. The full-length human USP1 protein consists of 785 amino acids, and its deubiquitinating enzyme activity mainly derives from the catalytic triad composed of Cys90, His593, and Asp751. USP1 itself is relatively inactive; it only achieves complete deubiquitinating enzyme activity when it binds to UAF1 (USP1-associated factor 1) to form a heterodimeric complex, thereby playing a role in DNA damage repair. Multiple studies have shown that USP1 is associated with tumor growth, survival, and differentiation. For example, the USP1 / UAF1 complex can stabilize proliferating cell nuclear antigen (PCNA) through deubiquitination, which plays a role in translesion synthesis (TLS) (T., Nijman, SM, Mirchandani, KD, Galardy, PJ, Cohn, MA, Haas, W., D'Andrea, AD (2006). Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol, 8(4), 339-347.). Fanconi anemia complement protein D2 (FANCD2) is a key protein in the Fanconi anemia (FA) pathway, and USP1 can stabilize FANCD2 through deubiquitination, thereby regulating the FA pathway. These cellular pathways play a crucial role in DNA damage repair induced by DNA cross-linking agents such as cisplatin and mitomycin C. DNA cross-linking repair requires deubiquitination of FANCD2 (Nijman, SM, Huang, TT, Dirac, AM, Brummelkamp, ​​TR, Kerkhoven, RM, D'Andrea, AD, & Bernards, R. (2005). The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell, 17(3), 331-339.). The DNA damage response (DDR) pathway regulated by PCNA and FANCD2 is essential for the repair of DNA damage induced by DNA cross-linking agents such as cisplatin, mitomycin C, diglycidyl, ionizing radiation, and ultraviolet radiation.

[0005] Studies in chicken DT40 cells involving the separate or combined knockout of USP1 and UAF1 showed that all three clones exhibited similar sensitivities to chemical cross-linking agents, the topoisomerase toxin camptothecin, and the poly(ADP-ribose) polymerase inhibitor (PARP), indicating that the USP1 / UAF1 complex is a regulator of cellular responses to DNA damage. Disruption of NHEJ in UAF1-deficient cells restored cellular resistance to camptothecin and PARP inhibitors. These results suggest that the USP1 / UAF1 complex promotes human renal replacement (HR), at least in part, by inhibiting NHEJ. (Murai, J., Yang, K., Dejsuphong, D., Hirota, K., Takeda, S., & D'Andrea, AD (2011). The USP1 / UAF1 complex promotes double-strand break repair through homologous recombination. Mol Cell Biol, 31(12), 2462-2469.)

[0006] The deubiquitinating enzyme USP1 promotes the stability of ID proteins and stem cell characteristics in osteosarcoma. USP1 binding and deubiquitination stabilize ID1, ID2, and ID3. USP1 promotes the maintenance of tumor stem cells and radiation resistance in glioblastoma by stabilizing ID1 and CHEK1, and regulates proliferation and differentiation by deubiquitination and stabilization of DNA-binding repressors (IDS) of antagonistic basic helix-loop-helix (BHLH) transcription factors. In osteosarcoma cells, knockout of the USP1 gene leads to ID protein instability, cell cycle arrest, and osteogenic differentiation. Conversely, high expression of USP1 in mesenchymal stem cells stabilizes ID proteins, inhibits osteoblast differentiation, and promotes proliferation. Furthermore, USP1 deficiency can lead to reduced bone mass in mice (Williams, SA, Maecker, HL, French, DM, Liu, J., Gregg, A., Silverstein, LB, Dixit, VM (2011). USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program inosteosarcoma. Cell, 146(6), 918-930.). In conclusion, small molecule inhibitors targeting USP1 and their use in compositions may become therapeutic methods for cancer and other USP1-related diseases. Summary of the Invention

[0007] This invention provides compounds of general formula (I) as USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof:

[0008]

[0009] in,

[0010] X is selected from: -S-, -O-, -NH-;

[0011] Y is selected from: -CH2-, -NR ya -、-C≡C-、-CH=CH-;

[0012] R ya Selected from: hydrogen, C1-C4 straight-chain alkyl groups;

[0013] Preferably, R ya Selected from: hydrogen, methyl, ethyl, propyl;

[0014] Preferably, R ya Selected from: hydrogen, methyl;

[0015] When Y is selected from -NR ya When -CH2-, n is 0 or 1;

[0016] When Y is selected from -C≡C- and -CH=CH-, n is 0;

[0017] R1 is selected from: -H, -NR 1a R 1b -OR 1c -CH2R 1d ;

[0018] R 1a R 1b R 1c R 1d They are the same or different and are independently selected from: hydrogen, C1-C4 straight-chain alkyl;

[0019] Preferably, R 1a R 1b R 1c R 1d They are either the same or different and are independently selected from: hydrogen, methyl, ethyl, propyl;

[0020] More preferably, R 1a R 1b R 1c R 1d They are either the same or different and are independently selected from: hydrogen, methyl, ethyl;

[0021] R2 is selected from phenyl or pyrimidinyl groups, wherein the phenyl or pyrimidinyl group is replaced by a substituent R. 2a To replace in the same or different ways once or multiple times;

[0022] R 2a Selected from: hydrogen, C1-C4 straight-chain alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halo-C1-C4 straight-chain alkyl or alkoxy, halo-C3-C4 branched alkyl or alkoxy, halo-C3-C4 cycloalkyl or alkoxy;

[0023] Preferably, R 2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

[0024] More preferably, R 2a Selected from: isopropyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropyl;

[0025] R3 is selected from: phenyl, wherein the phenyl is substituted with R 3a To replace in the same or different ways once or multiple times;

[0026] R 3a Selected from: hydrogen, pyrazolyl, imidazoleyl, triazoleyl; wherein the pyrazolyl, imidazoleyl, or triazoleyl group is substituted by substituent R4 once or multiple times in the same or different ways;

[0027] R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, halo-C3-C4 branched alkyl;

[0028] Preferably, R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and trichloromethyl;

[0029] More preferably, R4 is selected from: hydrogen, methyl, isopropyl, trifluoromethyl.

[0030] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0031] X is selected from: -S-, -O-, -NH-.

[0032] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0033] Y is selected from: -CH2-, -NH-, -NCH3-, -C≡C-, -CH=CH-.

[0034] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0035] R1 is selected from: -H, -NHCH3, -NCH3CH3, -OCH3, -CH3.

[0036] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0037] R2 is selected from: isopropylphenyl, isopropoxyphenyl, methoxyphenyl, trifluoromethoxyphenyl, cyclopropylmethoxypyrimidinyl.

[0038] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0039] R3 is selected from:

[0040]

[0041] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates, and / or isotope-substituted derivatives thereof, wherein:

[0042] When X is selected from: -S-

[0043] Y is selected from: -CH2-, -NR ya -、-C≡C-;

[0044] R ya Selected from: hydrogen, C1-C4 straight-chain alkyl groups;

[0045] Preferably, R ya Selected from: hydrogen, methyl, ethyl, propyl;

[0046] More preferably, R ya Selected from: hydrogen, methyl;

[0047] When Y is selected from -NR ya When -CH2-, n is 0 or 1;

[0048] When Y is selected from -C≡C-, n is 0;

[0049] R1 is selected from: -H, -NR 1a R 1b -OR 1c -CH2R 1d ;

[0050] R 1a R 1b R 1c R 1d They are the same or different and are independently selected from: hydrogen, C1-C4 straight-chain alkyl;

[0051] Preferably, R 1a R 1b R 1c R 1d They are the same or different and independently selected from: hydrogen, methyl, ethyl, propyl; more preferably, R 1a R 1b R 1c R 1d R1 is selected from the following groups, which are either the same or different and independent of each other: hydrogen, methyl, ethyl; R2 is selected from phenyl or pyrimidinyl, wherein the phenyl or pyrimidinyl group is replaced by a substituent R. 2a To replace in the same or different ways once or multiple times;

[0052] R 2a Selected from: hydrogen, C1-C4 straight-chain alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halo-C1-C4 straight-chain alkyl or alkoxy, halo-C3-C4 branched alkyl or alkoxy, halo-C3-C4 cycloalkyl or alkoxy;

[0053] Preferably, R 2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

[0054] More preferably, R 2a Selected from: isopropyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropyl;

[0055] R3 is selected from: phenyl, wherein the phenyl is substituted with R 3a To replace in the same or different ways once or multiple times;

[0056] R 3a Selected from: hydrogen, pyrazolyl, imidazoleyl, triazoleyl; wherein the pyrazolyl, imidazoleyl, or triazoleyl group is substituted by substituent R4 once or multiple times in the same or different ways;

[0057] R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, halo-C3-C4 branched alkyl;

[0058] Preferably, R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and trichloromethyl;

[0059] More preferably, R4 is selected from: hydrogen, methyl, isopropyl, trifluoromethyl;

[0060] X is selected from: -O- time,

[0061] Y is selected from: -CH2-, -C≡C-, -CH=CH-;

[0062] When Y is selected from -CH2-, n is 0 or 1;

[0063] When Y is selected from -C≡C- and -CH=CH-, n is 0;

[0064] R1 is selected from: -H;

[0065] R2 is selected from phenyl, wherein the phenyl is substituted with R 2a To replace in the same or different ways once or multiple times;

[0066] R 2a Selected from: hydrogen, C1-C4 straight-chain alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halo-C1-C4 straight-chain alkyl or alkoxy, halo-C3-C4 branched alkyl or alkoxy, halo-C3-C4 cycloalkyl or alkoxy;

[0067] Preferably, R 2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

[0068] More preferably, R 2a Selected from: isopropyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropyl;

[0069] More preferably, R 2a Selected from: isopropyl, trifluoromethoxy;

[0070] R3 is selected from: phenyl, wherein the phenyl is substituted with R 3a To replace in the same or different ways once or multiple times;

[0071] R 3aSelected from: hydrogen, pyrazolyl, imidazoleyl, triazoleyl; wherein the pyrazolyl, imidazoleyl, or triazoleyl is substituted by substituent R4 once or multiple times in the same or different ways; R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, halo-C3-C4 branched alkyl.

[0072] Preferably, R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and trichloromethyl;

[0073] More preferably, R4 is selected from: hydrogen, methyl, isopropyl, trifluoromethyl;

[0074] X is selected from: -NH-.

[0075] Y is selected from: -CH2-, -C≡C-;

[0076] When Y is selected from -CH2-, n is 0 or 1;

[0077] When Y is selected from -C≡C-, n is 0;

[0078] R1 is selected from: -H;

[0079] R2 is selected from phenyl, wherein the phenyl is substituted with R 2a To replace in the same or different ways once or multiple times;

[0080] R 2a Selected from: hydrogen, C1-C4 straight-chain alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halo-C1-C4 straight-chain alkyl or alkoxy, halo-C3-C4 branched alkyl or alkoxy, halo-C3-C4 cycloalkyl or alkoxy;

[0081] Preferably, R 2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

[0082] More preferably, R 2a Selected from: isopropyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropyl;

[0083] More preferably, R 2a Selected from: isopropyl, trifluoromethoxy;

[0084] R3 is selected from: phenyl, wherein the phenyl is substituted with R 3a To replace in the same or different ways once or multiple times;

[0085] R 3aSelected from: hydrogen, pyrazolyl, imidazoleyl, triazoleyl; wherein the pyrazolyl, imidazoleyl, or triazoleyl is substituted by substituent R4 once or multiple times in the same or different ways; R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, halo-C3-C4 branched alkyl.

[0086] Preferably, R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and trichloromethyl;

[0087] More preferably, R4 is selected from: hydrogen, methyl, isopropyl, trifluoromethyl.

[0088] In a preferred embodiment, the present invention relates to compounds of general formula (I) of USP1 inhibitors, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates and / or isotopically substituted derivatives, wherein: the compounds are selected from:

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] In another embodiment, the invention also relates to pharmaceutical compositions comprising one or more compounds of the above general formula (I) according to the invention, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates and / or isotope-substituted derivatives thereof.

[0097] In another embodiment, the invention also relates to pharmaceutical compositions comprising one or more compounds of the above general formula (I) according to the invention, or their enantiomers, diastereomers, tautomers, salts, crystal forms, solvates and / or isotopically substituted derivatives, and / or optionally pharmaceutically acceptable carriers, excipients or diluents.

[0098] In another embodiment, the invention also relates to a method for treating and / or preventing diseases or conditions caused by the activity of ubiquitin-specific protease 1 (USP1), the method comprising administering to a subject an effective amount of a compound relating to the above general formula (I), or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and / or isotope-substituted derivative thereof.

[0099] In another embodiment, the invention also relates to the use of a compound comprising one or more of the above general formula (I) according to the invention, or its enantiomers, diastereomers, tautomers, salts, crystal forms, solvates and / or isotope-substituted derivatives, for the preparation of a medicament for the treatment and / or prevention of diseases caused by ubiquitin-specific protease 1 (USP1) activity, including administering to a subject an effective amount of at least one compound according to the invention, or its enantiomers, diastereomers, tautomers, salts, crystal forms, solvates and / or isotope-substituted derivatives, or thereof.

[0100] In another embodiment, the invention also relates to a method for treating and / or preventing diseases or disorders caused by ubiquitin-specific protease 1 (USP1) activity, comprising administering to a subject an effective amount of at least one pharmaceutical composition according to the invention.

[0101] In another embodiment, the invention also relates to the use of a medicament comprising one or more of the above-described pharmaceutical compositions according to the invention for the preparation of a medicament for the treatment and / or prevention of diseases caused by ubiquitin-specific protease 1 (USP1) activity, including administering an effective amount of at least one pharmaceutical composition according to the invention to a subject.

[0102] In a preferred embodiment, the disease is: cancer, or a disease or condition related to DNA damage. Specifically, cancers associated with BRCA1 or BRCA2 mutations.

[0103] Universal synthetic route 1 for target molecules:

[0104]

[0105] Intermediate A-2 (R1 = H): Take 5g of raw material A-1, 4g of NaHCO3 (2.0 eq), and 50mL of methanol and add them to a 100mL reaction flask. Then add 250mg of 10% Pd / C and purge with hydrogen three times. After reacting at room temperature for 24h, add another 250mg of 10% Pd / C.

[0106] After reacting at room temperature for 24 hours, the intermediate A-2 was obtained by filtration of the diatomaceous earth.

[0107] Intermediate A-2 (R1 = NR) 1a R 1b ): Take raw material A-1 (5g, 1eq), secondary amine HNR 1a R 1b(1.1 eq) and TEA (2.2 eq) were added to a 100 mL reaction tube, followed by 50 mL of DMF. The reaction was carried out at 70 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and water was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was backwashed three times with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate A-2.

[0108] Intermediate A-4: Starting material A-2 (5 mmol, 1.0 eq), boric acid A-3 (7.5 mmol, 1.5 eq), Pd(dppf)₂Cl₂ (0.25 mmol, 0.05 eq), and K₂CO₃ (15 mmol, 3.0 eq) were sequentially added to a 50 mL reaction tube. 1,4-dioxane / water (v / v = 5:1, 10 mL) was added. The mixture was reacted under N₂ protection at 90 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, evaporated to dryness, and purified by silica gel column chromatography to obtain intermediate A-4.

[0109] Intermediate A-5: Add starting material A-4 (2 mmol, 1.0 eq) and NIS (4 mmol, 2.0 eq) to a 50 mL reaction tube, then add AcOH:TFA (v / v = 5:1, 10 mL), and heat under reflux for 12 h. Monitor by TLC; if the reaction is incomplete, add appropriate amounts of NIS and TFA. After the reaction is complete, cool to room temperature, pour the mixture into ice water, adjust the pH to 9-10 with sodium bicarbonate, extract three times with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, and separate by silica gel column chromatography to obtain intermediate A-5.

[0110] Target molecule A-7: Starting material A-5 (0.1 mmol, 1.0 eq), starting material acetylene A-6 (0.1 mmol, 1.0 eq), Pd(PPh3)2Cl2 (5% mol), and CuI (10% mol) were sequentially added to a 10 mL reaction tube. 1 mL of triethylamine was added, and the reaction was carried out under nitrogen protection at room temperature for 16 h. After the reaction was complete, the mixture was diluted with ethyl acetate, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate. Compound A-7 was obtained by preparative thin-layer chromatography.

[0111] Target molecule A-8: Take 10-20 mg of raw material A-7, dissolve it in methanol or ethyl acetate, add 3-5 mg of 10% Pd / C, replace with hydrogen three times, and react at room temperature for 6-12 h. After the reaction is complete, filter through diatomaceous earth, evaporate the organic phase to dryness, and purify by preparative thin-layer chromatography to obtain compound A-8.

[0112] Universal synthetic route 2 for target molecules:

[0113]

[0114] Intermediate B-2: 5g of starting material B-1, 1g of NaHCO3 (2.0 eq), and 50mL of methanol were added to a 100mL reaction flask, followed by the addition of 250mg of 10% Pd / C. The mixture was purged with hydrogen three times. After reacting at room temperature for 16h, the mixture was filtered through a diatomaceous earth filter and separated by silica gel column chromatography to obtain intermediate B-2 (610mg, 74% yield). 1 H NMR (400MHz, DMSO-d6) δ12.05 (s, 1H), 8.82 (d, J = 0.8Hz, 1H), 8.00 (t, J = 2.9Hz, 1H), 6.58 (ddd, J = 2.6, 1.6, 0.8Hz, 1H).

[0115] Intermediate B-3: Dissolve intermediate B-2 (0.61 g, 15 mmol) and (Boc)₂O (18 mmol, 1.2 eq) in 25 mL of THF, add TEA (22.5 mmol, 1.5 eq) and DMAP (0.15 mmol, 0.01 eq), and react at room temperature for 2 h. After the reaction is complete, directly mix with silica gel and purify by silica gel column chromatography to obtain intermediate B-3 (700 mg, 69% yield). 1 H NMR (500MHz, Chloroform-d) δ9.24 (s, 1H), 8.01 (s, 1H), 6.73 (dd, J = 3.7, 0.7Hz, 1H), 1.70 (s, 9H).

[0116] Intermediate B-4: Refer to the general synthetic route 1 for the synthetic method of intermediate A-4.

[0117] Intermediate B-5: The intermediate B-4 obtained above was dissolved in an appropriate amount of dichloromethane, and trifluoroacetic acid (TFA / DCM, v / v = 4:1) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, a large amount of solvent was removed under vacuum, and the mixture was diluted with dichloromethane. The mixture was placed in an ice bath, and the pH was adjusted to 9-10 with saturated sodium bicarbonate. The mixture was extracted three times with dichloromethane, and the organic phases were combined and purified by silica gel column chromatography to obtain compound B-5.

[0118] Intermediate B-6: The obtained compound B-5 (2.5 mmol, 1.0 eq) was dissolved in 5 mL of DMF, KOH (5 mmol, 2.0 eq) and elemental iodine (3 mmol, 1.2 eq) were added, and the reaction was carried out at room temperature for 1-6 h. After the reaction was completed, the mixture was quenched with water, diluted with ethyl acetate, and extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium thiosulfate, backwashed three times with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate B-6.

[0119] Target molecule B-7: Starting material B-6 (0.1 mmol, 1.0 eq), alkyne (0.1 mmol, 1.0 eq), Pd(PPh3)2Cl2 (5% mol), and CuI (10% mol) were sequentially added to a 10 mL reaction tube. Then, 0.5 mL of triethylamine and 0.5 mL of tetrahydrofuran were added. Under nitrogen protection, the reaction was carried out at 40 °C for 16 h. After the reaction was complete, the mixture was diluted with ethyl acetate, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate. Compound B-7 was obtained by preparative thin-layer chromatography.

[0120] Target molecule B-8: Refer to the procedure for synthesizing A-8 in General Synthetic Route 1.

[0121] General synthetic route 3 for target molecules:

[0122] The steps for general synthetic route 3 are the same as those for general synthetic route 1, only the order of reactions is different.

[0123]

[0124] Intermediate C-1 (R1 = OR 1c Weigh compound A-1 (1 equivalent), add 2 equivalents of R. 1c ONa was reacted with solvent MeOH at 80°C for 12 hours. After the reaction was completed, the mixture was concentrated and passed through a column to obtain C-1.

[0125] Intermediate C-1 (R1 = alkyl): Weigh compound A-1 (1 equivalent), 0.1 equivalent of Pd(dppf)2Cl2, 3 equivalents of K2CO3, and 1.1 equivalents of alkylboronic acid. Under vacuum and nitrogen atmosphere, add dioxane / H2O solvent and react at 90℃ for 12 h. After the reaction is complete, remove water with anhydrous sodium sulfate, concentrate the organic phase, and pass it through a column to obtain the alkylated product C-1.

[0126] Intermediate C-1 (R1 = NHR) 1b Weigh compound A-1 (1 equivalent), 2 equivalents of alkylamine hydrochloride, 3 equivalents of DIPEA, and DMF as solvent. React at 80°C for 12 h. After the reaction is complete, extract with EtOAc and saturated brine, collect the organic phase, concentrate, dry, and pass through a column to obtain the alkylamined product C-1.

[0127] Intermediate synthesis route 1:

[0128]

[0129] Intermediate F-2: 4 g of 1,1-dibromo-3,3,3-trifluoroacetone was added to a 10 mL reaction flask, followed by 1 g of sodium acetate and 2 mL of water. The reaction was carried out at 100 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and reaction solution 1 was reserved for later use. 3 g of terephthalaldehyde diacetaldehyde was added to a 250 mL reaction flask, followed by 10 mL of ammonia water and 50 mL of methanol, and then the above reaction solution 1 was added. The reaction was carried out at room temperature for 1 h, then heated to 100 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and a large amount of methanol was removed under vacuum. 50 mL of ethyl acetate was added for dilution. Subsequently, the mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography to obtain product F-2 (4 g, 88% yield). 1 H NMR(300MHz,Chloroform-d)δ7.81(dd,J=8.4,3.0Hz,2H),7.53(dd,J=8.3,2.5Hz,2H),7.43 (d, J=1.4Hz, 1H), 3.59 (tddd, J=16.5, 14.0, 7.1, 4.6Hz, 3H), 3.31 (s, 1H), 1.29-1.21 (m, 6H).

[0130] Intermediate F-3: Take a 25 mL reaction flask, add intermediate F-2 (1 g, 3.18 mmol) and 15 mL of anhydrous THF solution, place in an ice bath, and add 60% NaH (6.36 mmol, 2.0 eq). After stirring in an ice bath for 1 h, add the corresponding halogen (6.36 mmol, 2.0 eq), and then react from the ice bath to room temperature for 2 h. After the reaction is complete, dilute with THF, quench with water, and then extract three times with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain intermediate F-3.

[0131] Intermediate F-4: Dissolve the obtained intermediate F-3 in 10 ml of THF, and add 5 M HCl solution dropwise in an ice bath. After the addition is complete, allow the reaction to proceed at room temperature for 2 hours. After the reaction is complete, remove a large amount of THF solvent under vacuum. Dilute with ethyl acetate, and adjust the pH to 8-9 with saturated sodium bicarbonate solution. Extract three times with ethyl acetate, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain intermediate F-4, proceed directly to the next step.

[0132] Intermediate F-5: Take the intermediate F-4 obtained above, add K2CO3 (3.0 eq), 5 ml methanol, and Bestmann-Ohira reagent (1.5 eq) sequentially, and react at room temperature for 1 h. After the reaction is complete, directly mix the sample and pass it through a column. The intermediate F-5 is obtained by silica gel column chromatography.

[0133]

[0134] When the halogenated product in the synthesis step of intermediate F-3 is MeI, the compound F-5 obtained above is intermediate L-1 (R=Me) (180mg, 60% yield). 1 H NMR (300MHz, Chloroform-d) δ7.65-7.57 (m, 4H), 7.32 (q, J = 1.2Hz, 1H), 3.78 (s, 3H), 3.18 (s, 1H).

[0135]

[0136] When the halogenated product in the synthesis step of intermediate F-3 is iPrBr, the compound F-5 obtained above is intermediate L-2 (R = iPr) (200 mg, 66% yield). 1 H NMR (300MHz, Chloroform-d) δ7.63-7.55 (m, 2H), 7.52 (d, J = 2.5Hz, 2H), 7.43 (d, J = 1.3Hz, 1H), 4.55 (p, J = 6.7Hz, 1H), 1.46 (d, J = 6.7Hz, 6H).

[0137] Intermediate synthesis route 2:

[0138]

[0139] Intermediate F-7: Starting material F-6 (1 g, 5.60 mmol, hydrochloride form) was dissolved in 10 mL of hexafluoroisopropanol (HFIP), and starting material a (1.3 g, 1.5 eq) was added. TEA (1.2 g, 2.0 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. Upon completion of the reaction, water was added, and the mixture was diluted with ethyl acetate. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain intermediate F-7 (1 g, 53% yield). 1 H NMR (300MHz, Chloroform-d) δ7.87-7.76 (m, 2H), 7.73-7.59 (m, 2H), 6.52 (s, 1H), 2.44 (d, J = 0.8Hz, 3H).

[0140] Intermediate F-8: Take the above-obtained raw material F-7, add 5 ml of ethanol and 1 mL of 1N NaOH solution, heat the reaction to 80°C, and react for 16 h. After the reaction is complete, cool to room temperature, and slowly add 1M HCl solution dropwise in an ice bath until a solid precipitates. The pH should be 3-4. After filtration, remove water under vacuum to obtain compound F-8 (310 mg, 57% yield). 1H NMR (300MHz, Chloroform-d) δ8.34–8.16(m,2H),7.68–7.55(m,2H),6.51(s,1H),2.43(s,3H).

[0141] Intermediate F-9: The intermediate F-8 obtained above (310 mg, 1.15 mmol) was placed in a 25 mL reaction flask, and anhydrous THF solution (10 mL) was added. The reaction was carried out in an ice bath and cooled to 0 °C. Subsequently, lithium aluminum hydride (70 mg, 1.5 eq) was added, and the mixture was slowly heated to room temperature for 2 h. After the reaction was completed, the mixture was placed in an ice bath, diluted with tetrahydrofuran, quenched dropwise with ice water, filtered, dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain compound F-9 (290 mg). Proceed directly to the next step.

[0142] Intermediate F-10: Dissolve starting material F-9 in 5 mL of dichloromethane, add Dess-Martin reagent (1.2 eq), and react at room temperature for 2 h. After the reaction is complete, directly separate and purify compound F-10 (330 mg) by silica gel column chromatography, and proceed directly to the next step.

[0143] Intermediate L-3: See the synthesis method of intermediate F-5 to obtain compound L-3 (330 mg, 88% yield). 1 H NMR (300MHz, Chloroform-d) δ7.67-7.55 (m, 2H), 7.50-7.39 (m, 2H), 6.47 (s, 1H), 3.17 (s, 1H), 2.37 (d, J = 0.8Hz, 3H).

[0144] Intermediate synthesis route 3:

[0145]

[0146] Intermediate F-12: Take raw material F-11 (1g, 10.4mmol), raw material b (3.1g, 2.0eq), Cu(OAc)2 (1.9g, 1.0eq), TEA (2.1g, 2.0eq). Molecular sieve (500 mg) and 10 mL of dichloromethane were added sequentially to a 50 mL reaction flask, and the reaction was carried out overnight at 35-40 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to obtain compound F-12 (1 g, 75% yield). 1 H NMR (400MHz, Chloroform-d) δ 10.03 (s, 1H), 8.01-7.92 (m, 2H), 7.70-7.62 (m, 2H), 6.05 (s, 1H), 2.40 (d, J = 0.9Hz, 3H), 2.30 (s, 3H).

[0147] Intermediate L-4: See the method for synthesizing intermediate F-5 to obtain compound L-4 (500 mg, 51% yield). 1 H NMR (300MHz, Chloroform-d) δ 7.62-7.51 (m, 2H), 7.46-7.34 (m, 2H), 6.00 (s, 1H), 3.12 (s, 1H), 2.32 (d, J = 0.7Hz, 3H), 2.29 (s, 3H).

[0148] Intermediate synthesis route 4:

[0149]

[0150] Intermediate F-14: Starting material F-13 (500 mg, 1.97 mmol) was dissolved in 5 mL of methanol, and NaBH4 (112 mg, 1.5 eq) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and purified by silica gel column chromatography to obtain F-14 (450 mg, 89% yield). 1 H NMR (300MHz, Chloroform-d) δ7.56-7.48 (m, 2H), 7.38 (d, J = 8.2Hz, 2H), 7.30 (t, J = 1.3Hz, 1H), 4.71 (s, 2H), 3.73 (s, 3H).

[0151] Intermediate L-5: Dissolve the obtained F-14 in 5 mL of dichloromethane solution, add CBr4 (690 mg, 1.2 eq) and PPh3 (550 mg, 1.2 eq), and react at room temperature for 2 h. After the reaction is complete, remove a large amount of solvent, dilute with dichloromethane, wash twice with water, and purify by silica gel column chromatography to obtain L-5 (250 mg, 44% yield). 1 H NMR (300MHz, Chloroform-d) δ7.67-7.59 (m, 2H), 7.57-7.46 (m, 2H), 7.32 (d, J = 1.3Hz, 1H), 4.53 (s, 2H), 3.79 (s, 3H).

[0152] Intermediate synthesis route 5:

[0153]

[0154] Intermediate F-15: Following the synthetic method of intermediate F-2, compound F-15 (451 mg, 60% yield) was obtained. 1HNMR (400MHz, Chloroform-d) δ7.69 (d, J = 7.2 Hz, 2H), 7.39 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 1.53 (s, 9H).

[0155] Intermediate F-16: Compound F-16 (410 mg, 83% yield) was synthesized by referring to the method used to synthesize intermediate F-3. 1 HNMR (300MHz, Chloroform-d) δ7.59-7.54(m,2H),7.37-7.32(m,2H),7.28(q,J=1.2Hz,1H),3.74(s,3H),3.27(s,3H),1.45(s,9H).

[0156] Intermediate L-6: The obtained F-16 was dissolved in 10 mL of dichloromethane, and 3 mL of TFA was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, a large amount of solvent was removed under vacuum, and the mixture was diluted with dichloromethane. The pH was adjusted to 9-10 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the organic phases were combined and purified by silica gel column chromatography to obtain compound L-6 (251 mg, 85% yield). 1 H NMR (300MHz, Chloroform-d) δ7.48-7.41 (m, 2H), 7.24 (d, J = 1.1Hz, 1H), 6.67-6.62 (m, 2H), 3.73 (s, 3H), 2.88 (s, 3H).

[0157] Intermediate synthesis route 6:

[0158]

[0159] Intermediate F-17: Compound F-17 (1.1 g, 64% yield) was obtained by referring to the method for synthesizing intermediate F-2. 1 H NMR (500MHz, Chloroform-d) δ 11.13 (s, 1H), 8.27-8.23 (m, 2H), 8.06-8.01 (m, 2H), 7.53 (d, J = 1.7Hz, 1H).

[0160] Intermediate F-18: Compound F-18 (770 mg, 66% yield) was obtained by referring to the method for synthesizing intermediate F-3. 1 HNMR (300MHz, Chloroform-d) δ 8.38-8.29 (m, 2H), 7.90-7.82 (m, 2H), 7.39 (q, J = 1.2Hz, 1H), 3.86 (s, 3H).

[0161] Intermediate L-7: Dissolve the above-obtained compound F-18 in 10 mL of chloroform, add zinc powder (1.09 g, 4 eq), and add 0.5–1 mL of acetic acid dropwise. React at room temperature, and monitor the reaction on a TLC plate until completion. Filter, evaporate the organic phase to dryness, and purify by silica gel column chromatography to obtain L-7 (551 mg, 53% yield). 1 H NMR (400MHz, Chloroform-d) δ7.45-7.40 (m, 2H), 7.25 (d, J = 1.5Hz, 1H), 6.77-6.71 (m, 2H), 3.72 (s, 3H).

[0162] Example 1:

[0163]

[0164] Example 1 was synthesized using the procedure of General Synthesis Method 1: (30 mg, 73% yield). 1 ¹H NMR (500MHz, Chloroform-d) δ 9.41 (s, 1H), 8.23 ​​(s, 1H), 7.81 (dd, J = 7.7, 1.4Hz, 1H), 7.72–7.68 (m, 2H), 7.66 (d, J = 8.6Hz, 2H), 7.51 (dd, J = 8.0, 1.4Hz, 1H), 7.46 (td, J = 7.5, 1.5Hz, 1H), 7.35–7.31 (m, 2H), 3.81 (s, 3H), 3.68 (dt, J = 13.4, 6.7Hz, 1H), 1.35 (d, J = 6.9Hz, 6H); High-resolution mass spectrometry: C 28 H 22 F3N4S[M+H] + Calculated value: 503.15173, measured value: 503.15073.

[0165] Example 2:

[0166]

[0167] Example 2 was synthesized using the procedure of General Synthesis Method 1: (12 mg, 61% yield). 1¹H NMR (500MHz, Chloroform-d) δ 9.35 (s, 1H), 7.74 (dd, J = 7.7, 1.5Hz, 1H), 7.54 (dd, J = 6.4, 1.8Hz, 3H), 7.50 (dd, J = 8.0, 1.3Hz, 1H), 7.45 (td, J = 7.5, 1.5Hz, 1H), 7.34–7.31 (m, 1H), 7.31–7.27 (m, 3H), 3.75 (s, 3H), 3.66 (q, J = 6.8Hz, 1H), 3.34 (dd, J = 8.6, 6.7Hz, 2H), 3.18 (dd, J = 8.6, 6.7Hz, 2H), 1.30 (d, J = 6.9Hz, 6H); High-resolution mass spectrometry: C 28 H 26 F3N4S[M+H] + Calculated value: 507.18303, measured value: 507.18259.

[0168] Example 3:

[0169]

[0170] Example 3 (24 mg, 53% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR(400MHz,Chloroform-d)δ9.39(s,1H),8.22(s,1H),7.80(dd,J=7.7,1.5Hz,1H),7.71-7.66(m,2H),7.58-7.53(m,2H),7.51-7.46(m,1H),7.44( td,J=4.0,3.0,1.6Hz,2H),7.31(td,J=7.4,1.5Hz,1H),4.58(p,J=6.7Hz, 1H), 3.70-3.63 (m, 1H), 1.47 (d, J = 6.6Hz, 6H), 1.34 (d, J = 6.9Hz, 6H); mass spectrum: C 30 H 26 F3N4S[M+H] + Calculated value: 531.2, measured value: 531.3.

[0171] Example 4:

[0172]

[0173] Example 4 (9 mg, 65% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),7.74(dd,J=7.7,1.4Hz,1H),7.53(d,J=3 .6Hz,1H),7.51-7.48(m,1H),7.46-7.43(m,3H),7.40(d,J=1.3Hz,1H),7.35-7.30(m ,1H),7.28(s,2H),4.54(p,J=6.6Hz,1H),3.68-3.61(m,1H),3.33(dd,J=8.7,6.5Hz ,2H),3.17(dd,J=8.7,6.6Hz,2H),1.44(d,J=6.7Hz,6H),1.29(d,J=6.9Hz,6H); Mass spectrum: C 30 H 30 F3N4S[M+H] + Calculated value: 535.2, measured value: 535.3.

[0174] Example 5:

[0175]

[0176] Example 5 (20 mg, 46% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR (300MHz, Chloroform-d) δ9.40 (s, 1H), 8.23 ​​(s, 1H), 7.80 (dd, J = 7.7, 1.5Hz, 1H), 7.73-7.68 (m, 2H), 7.52-7. 44(m,4H),7.32(td,J=7.4,1.6Hz,1H),6.48(s,1H),3.70-3.61(m,1H),2.38(s,3H),1.34(d,J=6.8Hz,6H); Mass spectrum: C 28 H 21 F3N4SNa[M+Na] + Calculated value: 525.1, measured value: 525.2.

[0177] Example 6:

[0178]

[0179] Example 6 (6 mg, 52% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1H NMR(500MHz,Chloroform-d)δ9.36(s,1H),7.77-7.70(m,1H),7.57(s,1H),7.51(d,J=7.8Hz,1H),7.48-7.43(m,1H),7.37-7.32(m,3H),7.30(d ,J=8.1Hz,2H),6.45(s,1H),3.65(p,J=6.9Hz,1H),3.34(t,J=7.7Hz,2H),3.19(dd,J=8.8,6.6Hz,2H),2.32(s,3H),1.30(d,J=6.8Hz,6H); Mass spectrum: C 28 H 26 F3N4S[M+H] + Calculated value: 507.2, measured value: 507.1.

[0180] Example 7:

[0181]

[0182] Example 7 (19 mg, 51% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR(500MHz,Chloroform-d)δ9.40(s,1H),8.21(s,1H),7.81(dd,J=7.7,1.4Hz,1H),7.69-7.64(m,2H),7.51(dd,J=7.8,1.4Hz,1H),7.48 -7.43(m,3H),7.32(td,J=7.5,1.4Hz,1H),6.02(s,1H),3.70-3.65(m,1H),2.35(d,J=0.8Hz,3H),2.31(s,3H),1.34(d,J=6.8Hz,6H); Mass spectrum: C 28 H 25 N4S[M+H] + Calculated value: 449.2, measured value: 449.2.

[0183] Example 8

[0184]

[0185] Example 8 (6 mg, 49% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1H NMR(300MHz,Chloroform-d)δ9.34(s,1H),7.73(dd,J=7.7,1.5Hz,1H),7.54-7.48(m,2H),7.43(dd,J=7.8,1.5Hz,1H),7.36-7.29(m,3H),7.23(d,J= 8.4Hz,2H),5.97(s,1H),3.65(h,J=7.1Hz,1H),3.32(t,J=7.6Hz,2H),3.1 5(dd,J=8.6,6.5Hz,2H),2.28(d,J=7.3Hz,6H),1.29(d,J=6.8Hz,6H); Mass spectrum: C 28 H 29 N4S[M+H] + Calculated value: 453.2, measured value: 453.2.

[0186] Example 9

[0187]

[0188] Example 9 (33 mg, 84% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR(400MHz,Chloroform-d)δ9.38(s,1H),8.18(s,1H),7.82(dd,J=7.7,1.5Hz,1H),7.64-7.56(m,2H),7.51(dd,J=7 .9,1.4Hz,1H),7.45(td,J=7.5,1.5Hz,1H),7.39-7.29(m,4H),3.69(hept,J=6.8Hz,1H),1.35(d,J=6.9Hz,6H); Mass spectrum: C 23 H 19 N2S[M+H] + Calculated value: 355.1, Measured value: 355.1.

[0189] Example 10

[0190]

[0191] Example 10 (10 mg, 66% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ9.34(d,J=3.4Hz,1H),7.74(dd,J=7.7,1.5Hz,1H),7.56-7.41(m,3H),7.39-7.27(m,3H),7.23- 7.16(m,3H),3.63(tt,J=13.7,6.8Hz,1H),3.31(dd,J=8.9,6.5Hz,2H),3.11(dd,J=8.9,6.5Hz,2H),1.30(d,J=6.9Hz,6H); Mass spectrum: C 23 H 23 N2S[M+H] + Calculated value: 359.2, measured value: 359.0.

[0192] Example 11

[0193]

[0194] Example 11 (35 mg, 78% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(500MHz,Chloroform-d)δ9.40(s,1H),8.24(s,1H),8.02(s,1H),7.86(s,1H),7.80(d,J=7.7Hz,1H),7.75(q,J=8.4Hz ,4H),7.51(d,J=7.9Hz,1H),7.46(t,J=7.5Hz,1H),7.32(t,J=7.4Hz,1H),3.65(h,J=6.9Hz,1H),1.34(d,J=6.8Hz,6H); Mass spectrum: C 25 H 20 N5S[M+H] + Calculated value: 422.1, Measured value: 422.1.

[0195] Example 12

[0196]

[0197] Example 12 (5 mg, 27% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1H NMR(300MHz,Chloroform-d)δ9.35(s,1H),7.95(d,J=1.1Hz,1H),7.84(d,J=1.1Hz,1H),7.78-7.70(m,1H),7.69-7.60(m,2H),7.56(d,J=0.9Hz,1H ),7.55-7.41(m,2H),7.37-7.29(m,3H),3.62(h,J=6.8Hz,1H),3.34(dd,J =8.8, 6.4Hz, 2H), 3.19 (dd, J = 8.7, 6.4Hz, 2H), 1.29 (d, J = 6.9Hz, 6H); mass spectrum: C 25 H 24 N5S[M+H] + Calculated value: 426.2, measured value: 426.1.

[0198] Example 13

[0199]

[0200] Example 13 (25 mg, 56% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(400MHz,Chloroform-d)δ9.39(s,1H),8.23(s,1H),8.17(dd,J=7.6,1.9Hz,1H),7.71(d,J=8.4Hz,2H),7.65(d,J=8 .3Hz,2H),7.62(d,J=1.6Hz,1H),7.52(td,J=7.7,1.9Hz,1H),7.46-7.42(m,1H),7.31(d,J=1.5Hz,1H),3.78(s,3H); Mass spectrum: C 26 H 15 F6N4OS[M+H] + Calculated value: 545.1, measured value: 545.

[0201] Example 14

[0202]

[0203] Example 14 (11 mg, 81% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1¹H NMR (300 MHz, Chloroform-d) δ 9.35 (s, 1H), 8.10 (dd, J = 7.4, 2.1 Hz, 1H), 7.55–7.41 (m, 7H), 7.29 (s, 2H), 3.74 (s, 3H), 3.34 (t, J = 7.5 Hz, 2H), 3.18 (dd, J = 8.6, 6.4 Hz, 2H); Mass spectrometry: C 26 H 18 F6N4OSNa[M+Na] + Calculated value: 571.1, measured value: 571.2.

[0204] Example 15

[0205]

[0206] Example 15 (25 mg, 40% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(400MHz,Chloroform-d)δ9.40(s,1H),8.24(s,1H),8.18(dd,J=7.6,1.9Hz,1H),7.72(d,J=8.2Hz,2H),7.57(d,J=8.2H z,2H),7.54-7.49(m,1H),7.47(dd,J=7.5,1.5Hz,1H),7.45-7.42(m,2H),4.60(p,J=6.7Hz,1H),1.47(d,J=6.7Hz,6H); Mass spectrum: C 28 H 19 F6N4OS[M+H] + Calculated value: 573.1, measured value: 573.1.

[0207] Example 16

[0208]

[0209] Example 16 (10 mg, 73% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(500MHz,Chloroform-d)δ9.36(s,1H),8.12(dd,J=7.6,1.9Hz,1H),7.54(q,J=1.1Hz,1H),7.52(dd,J=7.7,2.1Hz,1H),7.48(dd,J=7.5,1.5Hz,1H),7.47 -7.43(m,3H),7.41(q,J=1.2Hz,1H),7.29(d,J=8.1Hz,2H),4.56(h,J=6.6Hz,1 H), 3.40-3.32 (m, 2H), 3.20 (dd, J=8.6, 6.7Hz, 2H), 1.44 (d, J=6.7Hz, 6H); Mass spectrum: C 28 H 23 F6N4OS[M+H] + Calculated value: 577.1, measured value: 577.2.

[0210] Example 17

[0211]

[0212] Example 17 (22 mg, 56% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 ¹H NMR (300 MHz, Chloroform-d) δ 9.40 (s, 1H), 8.24 (s, 1H), 8.17 (dd, J = 7.4, 2.0 Hz, 1H), 7.77–7.71 (m, 2H), 7.52–7.42 (m, 5H), 6.47 (s, 1H), 2.38 (s, 3H); Mass spectrometry: C 26 H 15 F6N4OS[M+H] + Calculated value: 545.1, measured value: 545.1.

[0213] Example 18

[0214]

[0215] Example 18 (12 mg, 87% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ9.36(s,1H),8.11(dd,J=7.4,2.0Hz,1H),7.56(s,1H),7.53-7.42(m,3H),7 .36-7.28(m,4H),6.44(s,1H),3.35(dd,J=8.8,6.3Hz,2H),3.20(dd,J=8.6,6.4Hz,2H),2.32(s,3H); Mass spectrum: C 26 H 18 F6N4OSNa[M+Na] + Calculated value: 571.1, measured value: 571.1.

[0216] Example 19

[0217]

[0218] Example 19 (18 mg, 48% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(400MHz,Chloroform-d)δ9.39(s,1H),8.22(s,1H),8.18(dd,J=7.7,1.9Hz,1H),7.75-7.66( m,2H),7.52(td,J=7.7,1.9Hz,1H),7.48-7.40(m,4H),6.01(s,1H),2.34(s,3H),2.30(s,3H); Mass spectrum: C 26 H 17 F3N4OSNa[M+Na] + Calculated value: 513.1, measured value: 513.1.

[0219] Example 20

[0220]

[0221] Example 20 (10 mg, 75% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(300MHz,Chloroform-d)δ9.35(s,1H),8.11(dd,J=7.3,2.1Hz,1H),7.56-7.41(m,5H),7.32(d,J=8.4Hz,2H), 7.23(d,J=2.0Hz,1H),5.98(s,1H),3.34(t,J=7.5Hz,2H),3.17(dd,J=8.6,6.5Hz,2H),2.28(d,J=7.3Hz,6H); Mass spectrum: C 26 H22 F3N4OS[M+H] + Calculated value: 495.1, measured value: 495.1.

[0222] Example 21:

[0223]

[0224] Example 21 (25 mg, 74% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(300MHz,Chloroform-d)δ9.40(s,1H),8.25(s,1H),8.18(dd,J=7.5,2.0Hz,1H ),8.03(d,J=1.2Hz,1H),7.86(d,J=1.2Hz,1H),7.77(s,4H),7.53-7.42(m,3H); Mass spectrum: C 23 H 13 F3N5OS[M+H] + Calculated value: 464.1, measured value: 464.0.

[0225] Example 22:

[0226]

[0227] Example 22 (10 mg, 82% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(300MHz,Chloroform-d)δ9.36(s,1H),8.10(d,J=7.4Hz,1H),7.95(s,1H),7.84(s,1H),7.64(d,J=8.0Hz ,2H),7.57(s,1H),7.55-7.41(m,3H),7.33(d,J=8.0Hz,2H),3.36(t,J=7.5Hz,2H),3.21(t,J=7.7Hz,2H); Mass spectrum: C 23 H 16 F3N5OSNa[M+Na] + Calculated value: 490.1, measured value: 490.1.

[0228] Example 23:

[0229]

[0230] Example 23 (17 mg, 31% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ7.96(s,1H),7.81(dd,J=7.7,1.5Hz,1H),7.64(q,J=8.4Hz,4H),7.47-7.35(m,2H),7 .33-7.29(m,1H),7.23(d,J=1.5Hz,1H),3.83(q,J=6.8Hz,1H),3.77(s,3H),3.48(s,6H),1.33(d,J=6.8Hz,6H); Mass spectrum: C 30 H 27 F3N5S[M+H] + Calculated value: 546.2, measured value: 546.2.

[0231] Example 24

[0232]

[0233] Example 24 (10 mg, 88% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(300MHz,Chloroform-d)δ7.76(dd,J=7.6,1.5Hz,1H),7.57-7.48(m,2H),7.47-7.34(m,2H),7.28(d,J=1.7Hz,3H),7.23(s,2 H), 3.81 (p, J = 6.8Hz, 1H), 3.74 (s, 3H), 3.45 (s, 6H), 3.25 (t, J = 7.5Hz, 2H), 3.14 (dd, J = 8.3, 6.1Hz, 2H), 1.29 (d, J = 6.9Hz, 6H); Mass spectrum: C 30 H 31 F3N5S[M+H] + Calculated value: 550.2, measured value: 550.3.

[0234] Example 25:

[0235]

[0236] Example 25 (16 mg, 28% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ7.97(s,1H),7.81(dd,J=7.7,1.5Hz,1H),7.71-7.66(m,2H),7.55-7.50(m,2H),7.47-7.42(m,2H),7.39(td,J=7. 5,1.5Hz,1H),7.23(d,J=1.5Hz,1H),4.57(h,J=6.7Hz,1H),3.79(h,J=6. 9Hz, 1H), 3.48 (s, 6H), 1.46 (d, J = 6.7Hz, 6H), 1.33 (d, J = 6.8Hz, 6H); mass spectrum: C 32 H 31 F3N5S[M+H] + Calculated value: 574.2, measured value: 574.2.

[0237] Example 26:

[0238]

[0239] Example 26 (5 mg, 44% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR(500MHz,Chloroform-d)δ7.76(dd,J=7.7,1.5Hz,1H),7.47-7.38(m,5H),7.30-7.27(m,2H),7.26(d,J=5.3Hz,2H),4.55(p,J=6.7Hz,1H ),3.82(p,J=6.8Hz,1H),3.46(s,6H),3.27(t,J=7.5Hz,2H),3.16(dd,J=8.5,6.5Hz,2H),1.44(d,J=6.7Hz,6H),1.30(d,J=6.8Hz,6H); Mass spectrum: C 32 H 35 F3N5S[M+H] + Calculated value: 578.3, measured value: 578.3.

[0240] Example 27

[0241]

[0242] Example 27 (15 mg, 29% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ7.95(s,1H),7.83(dd,J=7.7,1.5Hz,1H),7.67-7.63(m,2H),7.41(dq,J=7.9,6.7Hz,4H),7.28 (d,J=1.6Hz,1H),6.00(s,1H),3.88-3.76(m,1H),3.48(s,6H),2.33(d,J=0.8Hz,3H),2.30(s,3H),1.33(d,J=6.9Hz,6H); Mass spectrum: C 30 H 30 N5S[M+H] + Calculated value: 492.2, measured value: 492.3.

[0243] Example 28

[0244]

[0245] Example 28 (5 mg, 35% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 H NMR(300MHz,Chloroform-d)δ7.76(d,J=7.6Hz,1H),7.47-7.35(m,2H),7.30(d,J=7.9Hz,4H),7.23(d,J=7.5Hz,3H),5.97(s,1H), 3.82(d,J=8.5Hz,1H),3.46(s,6H),3.24(d,J=7.6Hz,2H),3.13(t,J=7.5Hz,2H),2.28(d,J=7.8Hz,6H),1.29(d,J=6.9Hz,6H); Mass spectrum: C 30 H 34 N5S[M+H] + Calculated value: 496.3, measured value: 496.3.

[0246] Example 29

[0247]

[0248] Example 29 (12 mg, 21% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ7.98(s,1H),7.82(dd,J=7.7,1.5Hz,1H),7.73-7.68(m,2H),7.47-7.41(m,3H),7.40-7.3 5(m,1H),7.28(d,J=1.5Hz,1H),6.47(s,1H),3.82(p,J=6.9Hz,1H),3.49(s,6H),2.37(s,3H),1.33(d,J=6.8Hz,6H); Mass spectrum: C 30 H 27 F3N5S[M+H] + Calculated value: 546.2, measured value: 546.2.

[0249] Example 30

[0250]

[0251] Example 30 (3.6 mg, 47% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(300MHz,Chloroform-d)δ7.75(dd,J=7.7,1.5Hz,1H),7.42(ddd,J=13.7,7.5,1.6Hz,2H),7.37-7.27(m,6H),6.44(s,1H),3.8 1(dt,J=13.7,6.8Hz,1H),3.46(s,6H),3.24(d,J=7.3Hz,2H),3.16(dd,J=8.1,5.7Hz,2H),2.31(s,3H),1.29(d,J=6.8Hz,6H); Mass spectrum: C 30 H 31 F3N5S[M+H] + Calculated value: 550.2, measured value: 550.3.

[0252] Example 31

[0253]

[0254] Example 31 (21 mg, 44% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1HNMR(300MHz,Chloroform-d)δ7.99(d,J=10.0Hz,2H),7.88-7.78(m,2H),7.72(s,4H),7.4 9-7.35(m,2H),7.28(s,1H),3.81(p,J=6.8Hz,1H),3.48(s,6H),1.33(d,J=6.9Hz,6H); Mass spectrum: C 27 H 25 N6S[M+H] + Calculated value: 465.2, measured value: 465.3.

[0255] Example 32

[0256]

[0257] Example 32 (11 mg, 86% yield) was synthesized following the procedure of General Synthesis Method 1. Structural characterization: 1 HNMR(500MHz,Chloroform-d)δ7.90(d,J=57.6Hz,2H),7.76(d,J=7.6Hz,1H),7.62(d,J=8.0Hz,2H),7.46(d,J=7.8Hz,1H),7.40(t,J=7.5Hz,1H ),7.33(d,J=8.1Hz,2H),7.29(s,2H),3.88-3.78(m,1H),3.47(s,6H),3.27(t,J=7.5Hz,2H),3.17(t,J=7.5Hz,2H),1.30(d,J=6.9Hz,6H); Mass spectrum: C 27 H 29 N6S[M+H] + Calculated value: 469.2, measured value: 469.3.

[0258] Example 33

[0259]

[0260] Example 33 (21 mg, 23% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1H NMR(300MHz,Chloroform-d)δ11.48(s,1H),8.77(s,1H),7.57(dd,J=18.0,7.6Hz,3H),7.49-7.33(m,6H),7.2 3(d,J=7.4Hz,1H),4.53(p,J=6.7Hz,1H),3.44-3.31(m,1H),1.44(d,J=6.7Hz,6H),1.21(d,J=6.8Hz,6H); Mass spectrum: C 30 H 27 F3N5[M+H] + Calculated value: 514.2, measured value: 514.3.

[0261] Example 34

[0262]

[0263] Example 34 (5 mg, 40% yield) was synthesized according to the procedure of General Synthesis Method 2. Structural characterization: 1 H NMR(400MHz,Chloroform-d)δ10.07(s,1H),8.67(s,1H),7.62(d,J=7.5Hz,1H),7.42(q,J=6.3,4.8Hz,5H),7.29(d,J=7.6Hz,3H),7.0 4(s,1H),4.53(p,J=6.7Hz,1H),3.52(q,J=6.8Hz,1H),3.18(dd,J=14.7,6.1Hz,4H),1.44(d,J=6.8Hz,6H),1.25(d,J=6.8Hz,6H); Mass spectrum: C 30 H 31 F3N5[M+H] + Calculated value: 518.2, measured value: 518.4.

[0264] Example 35

[0265]

[0266] Example 35 (9 mg, 84% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1H NMR(500MHz,Chloroform-d)δ10.03(s,1H),8.65(s,1H),7.63(dd,J=7.6,1.5Hz,1H),7.51(d,J=7.9Hz,2H),7.48-7.45(m,1H),7.43–7.38(m,1H),7.34 -7.31(m,1H),7.30-7.27(m,3H),7.09(s,1H),3.74(s,3H),3.55-3.49(m,1 H), 3.22 (t, J = 7.2Hz, 2H), 3.15 (t, J = 7.2Hz, 2H), 1.25 (d, J = 6.8Hz, 6H); Mass spectrum: C 28 H 27 F3N5[M+H] + Calculated value: 490.2, measured value: 490.3.

[0267] Example 36

[0268]

[0269] Example 36 (30 mg, 59% yield) was synthesized according to the procedure of General Synthesis Method 2. Structural characterization: 1 H NMR(300MHz,Chloroform-d)δ12.03(s,1H),8.54(s,1H),7.64-7.50(m,2H),7.44(d,J =4.3Hz, 2H), 7.23 (d, J = 10.5Hz, 6H), 3.25 (p, J = 7.0Hz, 1H), 1.14 (d, J = 7.0Hz, 6H); Mass spectrum: C 23 H 20 N3[M+H] + Calculated value: 338.2, measured value: 338.1.

[0270] Example 37

[0271]

[0272] Example 37 (5 mg, 53% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1H NMR(400MHz,Chloroform-d)δ9.06(s,1H),8.90(s,1H),7.62(d,J=7.7Hz,1H),7.44(dd,J=18.0,7.7Hz,2H),7.30(s,1H),7. 24(s,2H),7.22-7.09(m,4H),3.52(q,J=7.0Hz,1H),3.17(t,J=7.4Hz,2H),3.09(t,J=7.7Hz,2H),1.24(d,J=7.4Hz,6H); Mass spectrum: C 23 H 24 N3[M+H] + Calculated value: 342.2, measured value: 342.2.

[0273] Example 38

[0274]

[0275] Example 38 (21 mg, 30% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1 H NMR (300MHz, DMSO-d6) δ9.07(d,J=1.2Hz,1H),8.87(d,J=1.3Hz,1H),8.34(s,1H),8.02-7.90(m,3H),7.75-7.65(m,2H ),7.54(dd,J=7.6,1.5Hz,1H),7.48-7.36(m,2H),7.31-7.22(m,1H),3.47(d,J=6.7Hz,1H),1.19(d,J=6.9Hz,6H); Mass spectrum: C 25 H 21 N6[M+H] + Calculated value: 405.2, measured value: 405.1.

[0276] Example 39

[0277]

[0278] Example 39 (7 mg, 55% yield) was synthesized according to the procedure of General Synthesis Method 2. Structural characterization: 1H NMR(500MHz,Chloroform-d)δ9.60(s,1H),8.83(s,1H),7.96(s,1H),7.85(s,1H),7.61(t,J=8.5Hz,3H),7.44(dd,J=23.2,7.8H z,2H),7.30(d,J=7.9Hz,3H),7.15(s,1H),3.51(q,J=6.9Hz,1H),3.19(dp,J=11.0,5.6,4.8Hz,4H),1.25(d,J=7.3Hz,6H); Mass spectrum: C 25 H 25 N6[M+H] + Calculated value: 409.2, measured value: 409.4.

[0279] Example 40

[0280]

[0281] Example 40 (33 mg, 45% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1 H NMR(500MHz,Chloroform-d)δ12.16(s,1H),8.54(s,1H),7.55(d,J=8.6Hz,2H),7.49-7.37(m,4H),7.31(d,J=8.2Hz,2H), 7.23(td,J=7.3,1.7Hz,1H),5.99(s,1H),3.34(hept,J=6.8Hz,1H),2.31(s,3H),2.25(s,3H),1.16(d,J=6.8Hz,6H); Mass spectrum: C 28 H 26 N5[M+H] + Calculated value: 432.2, measured value: 432.3.

[0282] Example 41

[0283]

[0284] Example 41 (6 mg, 48% yield) was synthesized according to the procedure of General Synthesis Method 2. Structural characterization: 1H NMR (300MHz, Chloroform-d) δ10.23(s,1H),8.69(s,1H),7.61(dd,J=7.6,1.4Hz,1H),7.53-7.36(m,2H),7.33-7.27(m,3H),7.21(d,J=8. 3Hz,2H),7.03(s,1H),5.99(s,1H),3.58-3.40(m,1H),3.15(dq,J=11.7,6.3Hz,4H),2.31(s,3H),2.26(s,3H),1.23(d,J=6.8Hz,6H); Mass spectrum: C 28 H 30 N5[M+H] + Calculated value: 436.2, measured value: 436.3.

[0285] Example 42

[0286]

[0287] Example 42 (22 mg, 25% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1 H NMR(300MHz,Chloroform-d)δ12.08(s,1H),8.59(s,1H),7.73-7.66(m,1H),7.62(s,1H),7.57-7.49(m,2H),7.44-7.41(m, 2H),7.33(d,J=8.4Hz,2H),7.25-7.20(m,1H),6.42(s,1H),3.34(p,J=6.8Hz,1H),2.29(s,3H),1.17(d,J=6.8Hz,6H); Mass spectrum: C 28 H 21 F3N5[MH] - Calculated value: 484.2, measured value: 484.1.

[0288] Example 43

[0289]

[0290] Example 43 (9 mg, 69% yield) was synthesized following the procedure outlined in General Synthesis Method 2. Structural characterization: 1H NMR (400MHz, Chloroform-d) δ9.57(s,1H),8.80(s,1H),7.62(dd,J=7.7,1.5Hz,1H),7.46(dd,J=8.0,1.5Hz,1H),7.41(td,J=7.5,1. 5Hz,1H),7.33-7.26(m,5H),7.08(s,1H),6.45(s,1H),3.55-3.44(m,1H),3.23-3.12(m,4H),2.31(s,3H),1.24(d,J=6.9Hz,6H); Mass spectrum: C 28 H 27 F3N5[M+H] + Calculated value: 490.2, measured value: 490.3.

[0291] Example 44:

[0292]

[0293] The synthesis of Example 44 was carried out in accordance with the general synthesis method 2. 1 H NMR (300MHz, CDCl3) δ8.95 (s, 1H), 8.07 (dd, J = 7.4, 2.0Hz, 1H), 7.88 (s, 1H), 7.48 (ddd, J=9.4,7.3,2.8Hz,4H),7.40(d,J=8.1Hz,1H),7.35–7.30(m,3H). Mass spectrum: C21H12F3N3O[M+H] + Calculated value: 380.3, measured value: 380.1.

[0294] Example 45

[0295]

[0296] Refer to the general synthesis method 2 for the synthesis example 45. 1 ¹H NMR (400MHz, CDCl₃) δ 8.96 (s, 1H), 8.01 (dd, J = 7.4, 2.0Hz, 1H), 7.52–7.38 (m, 2H), 7.27 (d, J = 1.5Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 7.6, 3.6Hz, 2H), 3.23–3.17 (m, 2H), 3.14–3.08 (m, 2H). Mass spectrometry: C₂¹H¹⁶F₃N₃O [M+H] + Calculated value: 386.1, measured value: 386.1.

[0297] Example 46

[0298]

[0299] Refer to the general synthesis method 2 operation method to synthesize Example 46. 1 ¹H NMR (300MHz, CDCl₃) δ 10.46 (s, 1H), 9.01 (s, 1H), 8.15–7.99 (m, 2H), 7.90 (d, J = 18.3 Hz, 2H), 7.68 (dd, J = 29.3, 8.2 Hz, 4H), 7.46 (dd, J = 15.9, 7.8 Hz, 3H). Mass spectrometry: C₂₃H₁₃F₃N₆O [M+H] + Calculated value: 447.1, measured value: 447.1.

[0300] Example 47

[0301]

[0302] Refer to the general synthesis method 2 operation method for synthesis example 47. 1 H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 8.90 (s, 1H), 8.00 (dd, J = 7.3, 1.9Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H) ,7.59(d,J=8.3Hz,2H),7.48–7.37(m,3H),7.29(d,J=8.3Hz,2H),3.21(s,4H). Mass spectrum: C23H17F3N6O[M+H] + Calculated value: 451.1, measured value: 451.1.

[0303] Example 48

[0304]

[0305] Refer to the general synthesis method 2 operation method to synthesize Example 48. 1 ¹H NMR (400MHz, CDCl₃) δ 9.06 (s, 1H), 8.07 (dd, J = 7.4, 1.8Hz, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.6Hz, 2H), 7.50–7.36 (m, 5H), 6.47 (s, 1H), 2.37 (s, 3H). Mass spectrometry: C₂₆H₁₅N₅OF₆ [M+H] + Calculated value: 528.4, measured value: 528.1.

[0306] Example 49

[0307]

[0308] Refer to the general synthesis method 2 operation method to synthesize Example 49. 1 H NMR(300MHz, CDCl3)δ9.19(s,1H),8.92(s,1H),8.03(dd,J=7.1,2.1Hz,1H),7.51–7.39(m,3H),7.3 3(dd,J=9.8,3.5Hz,4H),7.22(s,1H),6.47(s,1H),3.22(s,4H),2.33(s,3H). Mass spectrum: C26H19F6N5O[M+H] + Calculated value: 532.1, measured value: 532.1.

[0309] Example 50

[0310]

[0311] Refer to the general synthesis method 2 operation method to synthesize Example 50. 1 ¹H NMR (400MHz, CDCl₃) δ 8.95 (s, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.47–7.36 (m, 3H), 7.32 (s, 1H), 3.78 (s, 3H). Mass spectrometry: C₂₆H₁₅F₆N₅O [M⁻¹] - Calculated value: 526.1, Measured value: 526.1.

[0312] Example 51

[0313]

[0314] Refer to the general synthesis method 2 operation method to synthesize Example 51. 1 H NMR(400MHz, CDCl3)δ8.86(s,1H),8.03–7.96(m,1H),7.47–7.37(m,6H),7.2 4(s,2H),7.12(s,1H),3.48(s,3H),3.23–3.15(m,4H); Mass spectrum: C26H19N5OF6[M+H] + Calculated value: 532.45, measured value: 532.1.

[0315] Example 52

[0316]

[0317] Refer to the general synthesis method 2 for the synthesis of Example 52. 1¹H NMR (300MHz, CDCl₃) δ 8.86 (s, 1H), 8.02 (d, J = 6.1 Hz, 1H), 7.67 (s, 1H), 7.56–7.33 (m, 8H), 6.04 (s, 1H), 2.35 (s, 3H), 2.31 (s, 3H). Mass spectrometry: C₂₆H₁₈N₅OF₃ [M+H] + Calculated value: 474.45, measured value: 473.9.

[0318] Example 53

[0319]

[0320] Refer to the general synthesis method 2 operation method to synthesize Example 53. 1 H NMR (500MHz, CDCl3) δ10.35(s,1H),8.71(s,1H),8.01(d,J=6.5Hz,1H),7.43(dt,J=23.7,8.2Hz,4H),7.29(d,J=8.0Hz,2H),7 .21(d,J=7.9Hz,2H),7.07(s,1H),6.00(s,1H),3.18(dd,J=19.9,6.2Hz,4H),2.33(s,3H),2.26(s,4H). Mass spectrum: C26H22F3N5O[M+H] + Calculated value: 478.2, measured value: 478.1.

[0321] Example 54

[0322]

[0323] Refer to the general synthesis method 2 operation method to synthesize Example 54. 1 H NMR(300MHz, CDCl3)δ9.19(s,1H),8.92(s,1H),8.03(dd,J=7.1,2.1Hz,1H),7.51–7.39(m,3H),7.3 3(dd,J=9.8,3.5Hz,4H),7.22(s,1H),6.47(s,1H),3.22(s,4H),2.33(s,3H). Mass spectrum: C28H22F3N5O[M+H] + Calculated value: 556.47, measured value: 556.0.

[0324] Example 55

[0325]

[0326] Refer to the general synthesis method 2 for the synthesis example 55. 1¹H NMR (300MHz, MeOD) δ 8.91 (s, 1H), 7.89 (dd, J = 7.1, 1.5Hz, 2H), 7.66–7.54 (m, 3H), 7.50–7.35 (m, 5H), 4.53 (dt, J = 13.3, 6.7Hz, 1H), 3.22 (dd, J = 9.2, 5.2Hz, 4H), 1.46 (s, 3H), 1.44 (s, 3H); Mass spectrometry: C₂₈H₂₆F₃N₅O [M+H] + Calculated value: 560.5, measured value: 560.2.

[0327] Example 56

[0328]

[0329] Synthesize Example 56 (21 mg, 80% yield) according to the procedure of General Synthesis Method 1. 1 ¹H NMR (500MHz, CDCl₃) δ 9.06 (s, 1H), 8.24 (s, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.61–7.56 (m, 2H), 7.50–7.46 (m, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.39–7.35 (m, 3H), 7.30 (td, J = 7.5, 1.3 Hz, 1H), 3.51 (dt, J = 13.7, 6.9 Hz, 1H), 1.30 (s, 3H), 1.29 (s, 3H) ppm; High-resolution mass spectrometry: C₂₃H₁₈N₂O [M+H] + Calculated value: 339.14919, measured value: 339.14926.

[0330] Example 57

[0331]

[0332] Synthesize Example 57 (7.5 mg, 65% yield) according to the procedure of General Synthesis Method 1. 1 ¹H NMR (500MHz, CDCl₃) δ 8.97 (s, 1H), 7.65 (t, J = 3.2Hz, 2H), 7.51–7.46 (m, 1H), 7.46–7.39 (m, 1H), 7.34–7.27 (m, 3H), 7.23–7.15 (m, 3H), 3.51 (dq, J = 13.7, 6.8Hz, 1H), 3.17–3.06 (m, 4H), 1.29 (s, 3H), 1.27 (s, 3H) ppm; High-resolution mass spectrometry: C₂₃H₂₂N₂O [M+H] + Calculated value: 343.18049, measured value: 343.18051.

[0333] Example 58

[0334]

[0335] Synthesize Example 58 (38 mg, 70% yield) according to the procedure of General Synthesis Method 1. 1 H NMR (500MHz, CDCl3) δ9.06 (s, 1H), 8.06 (d, J = 2.2Hz, 1H), 7.82 (d, J = 1.8Hz, 1H), 7.65–7.58 (m, 5H), 7.47 (d, J = 8.1Hz, 1H), 7.33 (s ,1H),7.07(dd,J=2.2,0.7Hz,1H),3.80(s,3H),3.50(dt,J=13.7,6.8Hz,1H),1.24(s,3H),1.23(s,3H)ppm; Mass spectrum: C28H21F3N4O[M+H] + Calculated value: 487.2, measured value: 487.2.

[0336] Example 59

[0337]

[0338] Example 59 (10.5 mg, 62% yield) was synthesized according to the procedure of General Synthesis Method 1. 1 H NMR (500MHz, CDCl3) δ8.96 (s, 1H), 7.96 (d, J = 2.1Hz, 1H), 7.47 (d, J = 8.1Hz, 2H ),7.37(d,J=1.4Hz,1H),7.29(d,J=8.0Hz,1H),7.23(d,J=8.1Hz,3H),7.16(d d,J=8.0,1.5Hz,1H),6.98(d,J=1.9Hz,1H),3.68(s,3H),3.34(dq,J=13.7,6. 8Hz,1H),2.99–2.83(m,4H),1.13(d,J=6.9Hz,6H)ppm; Mass spectrum: C28H25F3N4O[M+H] + Calculated value: 491.2, measured value: 491.2.

[0339] Example 60

[0340]

[0341] Example 60 (37 mg, 70% yield) was synthesized according to the procedure of General Synthesis Method 1. 1H NMR(500MHz, CDCl3)δ9.07(s,1H),8.06(d,J=2.2Hz,1H),8.02(s,1H),7.88(s,1H),7.83(s,1H),7.78–7.72(m,2H),7.70–7.64(m,2H),7.6 1(dd,J=8.1,1.4Hz,1H),7.47(d,J=8.2Hz,1H),7.08(d,J=1.9Hz,1H),3.55–3.44(m,1H),1.25(s,3H),1.23(s,3H)ppm; Mass spectrum: C25H19N5O[M+H] + Calculated value: 406.2, measured value: 404.2.

[0342] Example 61

[0343]

[0344] Example 61 (14.5 mg, 68% yield) was synthesized according to the procedure of General Synthesis Method 1. 1 H NMR (500MHz, CDCl3) δ9.05 (s, 1H), 8.05 (d, J = 2.2Hz, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.65 (d, J = 8.4Hz, 2H), 7.45 (d, J = 1.7Hz, 1H), 7.37 (dd, J = 14.4, 8. 2Hz,3H),7.24(d,J=8.1Hz,1H),7.06(d,J=1.9Hz,1H),3.47–3.36(m,1H), 3.01(dq,J=9.6,6.1Hz,4H),1.21(d,J=6.9Hz,6H)ppm; Mass spectrum: C25H21N5O[M+H] + Calculated value: 410.2, measured value: 410.2.

[0345] Example 62

[0346]

[0347] Example 62 (36 mg, 76% yield) was synthesized according to the procedure of General Synthesis Method 1. 1H NMR(500MHz, CDCl3)δ9.05(d,J=0.6Hz,1H),8.05(d,J=2.2Hz,1H),7.82(t,J=2.4Hz,1H),7.61–7.57(m,3H),7.45(dd,J=10.0,8.4Hz,3H ),7.07(dd,J=2.2,0.7Hz,1H),6.04(s,1H),3.50(dt,J=13.7,6.8Hz,1H),2.34(s,6H),1.24(s,3H),1.23(s,3H)ppm; Mass spectrum: C28H24N4O[M+H] + Calculated value: 433.2, Measured value: 433.2.

[0348] Example 63

[0349]

[0350] Synthesize Example 63 (9 mg, 50% yield) according to the procedure of General Synthesis Method 1. 1 H NMR (400MHz, CDCl3) δ8.95(s,1H),7.95(d,J=2.1Hz,1H),7.37(s,1H),7.27(dd,J=17.7,8.2Hz,3H),7.21–7.14(m,4H),6.97(d,J=1.5Hz,1H ),5.90(s,1H),3.33(dt,J=13.5,6.8Hz,1H),2.94–2.85(m,4H),2.22(s,3H),2.19(s,3H),1.14(s,3H),1.12(s,3H)ppm; Mass spectrum: C28H28N4O[M+H] + Calculated value: 437.2, measured value: 437.2.

[0351] Example 64

[0352]

[0353] Synthesize Example 64 (30 mg, 58% yield) according to the procedure of General Synthesis Method 1. 1H NMR (400MHz, CDCl3) δ8.97(s,1H),7.97(d,J=2.2Hz,1H),7.74(d,J=1.7Hz,1H),7 .53(td,J=6.3,3.2Hz,3H),7.45(d,J=8.4Hz,2H),7.38(d,J=8.2Hz,1H),7.36(d,J =1.0Hz,1H),7.02–6.94(m,1H),4.51(hept,J=6.7Hz,1H),3.42(hept,J=6.8Hz,1 H),1.40(s,3H),1.39(s,3H),1.16(s,3H),1.14(s,3H)ppm; Mass spectrum: C30H25F3N4O[M+H] + Calculated value: 515.2, measured value: 515.2.

[0354] Example 65

[0355]

[0356] Synthesize Example 65 (3 mg, 30% yield) according to the procedure of General Synthesis Method 1. 1 H NMR (500MHz, CDCl3) δ8.29(s,1H),7.46(d,J=8.0Hz,2H),7.40(d,J=12.4Hz,2H),7.34( d,J=8.0Hz,1H),7.31(d,J=8.0Hz,2H),7.21(d,J=8.0Hz,1H),4.77(t,J=8.9Hz,2H),4.5 8(dt,J=13.3,6.7Hz,1H),3.44(t,J=9.0Hz,2H),3.38(dd,J=13.8,6.8Hz,1H),2.98(dq, J=9.8,5.9Hz,4H),1.46(d,J=6.7Hz,6H),1.20(d,J=6.9Hz,6H)ppm; Mass spectrum: C30H29N4O[M+H] + Calculated value: 519.3, measured value: 519.3.

[0357] Example 66

[0358]

[0359] Example 66 (32 mg, 62% yield) was synthesized according to the procedure of General Synthesis Method 1. 1¹H NMR (500MHz, CDCl₃) δ 9.07 (s, 1H), 8.07 (d, J = 2.2Hz, 1H), 7.82 (s, 1H), 7.62 (dd, J = 12.4, 8.4Hz, 3H), 7.46 (dd, J = 12.9, 8.4Hz, 3H), 7.08 (d, J = 2.0Hz, 1H), 6.48 (s, 1H), 3.54–3.45 (m, 1H), 2.39 (d, J = 0.5Hz, 3H), 1.24 (d, J = 6.8Hz, 6H) ppm; Mass spectrometry: C₂₈H₂₁F₃N₄O[M+H] + Calculated value: 487.17412, measured value: 487.17416.

[0360] Example 67

[0361]

[0362] Synthesize Example 67 (3 mg, 28% yield) according to the procedure of General Synthesis Method 1. 1 H NMR (400MHz, CDCl3) δ8.97(s,1H),7.96(d,J=2.2Hz,1H),7.36(d,J=1.5Hz,1H),7.30(d,J=8.0Hz,1H),7.27–7.22(m,4H),7.16(d,J=8.1Hz,1H),6. 98(d,J=1.6Hz,1H),6.36(s,1H),3.32(dt,J=13.7,6.9Hz,1H),2.97–2.86 (m,4H),2.24(s,3H),1.13(d,J=6.9Hz,6H)ppm; high resolution mass spectrum: C28H25F3N4O[M+H] + Calculated value: 491.2, measured value: 491.2.

[0363] Example 68

[0364]

[0365] Synthesize Example 68 (22 mg, 50% yield) according to the procedure of General Synthesis Method 1. 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.20 (s, 1H), 8.03 (dd, J = 7.6, 1.9Hz, 1H), 7.65–7.59 ( m,4H),7.47–7.33(m,3H),7.27(d,J=0.9Hz,1H),3.75(s,3H)ppm; Mass spectrum: C26H14F6N4O2[M+H] +Calculated value: 529.1, measured value: 529.1.

[0366] Example 69

[0367]

[0368] The compound 7-(phenylethynyl)-2-(2-(trifluoromethoxy)phenyl)furan[3,2-d]pyrimidine was synthesized following the procedure of General Synthesis Method 1. (14 mg, 37% yield). 1 ¹H NMR (400MHz, Chloroform-d) δ 9.10 (s, 1H), 8.26 (s, 1H), 8.06 (dd, J = 7.7, 1.8Hz, 1H), 7.64–7.58 (m, 2H), 7.52 (ddd, J = 8.1, 7.5, 1.9Hz, 1H), 7.48–7.40 (m, 2H), 7.40–7.34 (m, 3H). The obtained compound was dissolved in ethyl acetate, and 2 mg of Lindra catalyst was added. The mixture was purged with hydrogen three times and reacted at room temperature for 4 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, the organic phase was evaporated to dryness, and purified by preparative thin-layer chromatography to obtain the target molecule, Example 69 (3 mg, 28% yield). 1 H NMR(400MHz,Chloroform-d)δ9.04(s,1H),8.14(d,J=16.3Hz,1H),8.11-8.08(m,1H),8.07(s,1H),7.56(ddd,J=7.9,4.6,1.7Hz, 2H),7.52(dd,J=7.7,2.0Hz,1H),7.50-7.43(m,2H),7.38(dd,J=8.3,6.8Hz,2H),7.32-7.28(m,1H),7.15(d,J=16.3Hz,1H); Mass spectrum: C 21 H 14 F3N2O2[M+H] + Calculated value: 383.1, measured value: 383.1.

[0369] Example 70

[0370]

[0371] Example 70 (9.8 mg, 67% yield) was synthesized using the procedure described in Example 69. 1¹H NMR (500MHz, CDCl₃) δ 9.00 (s, 1H), 7.93 (dd, J = 7.6, 1.8Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.2Hz, 2H), 7.49 (d, J = 8.0Hz, 3H), 7.46–7.37 (m, 2H), 7.33 (s, 1H), 6.95 (d, J = 12.1Hz, 1H), 6.86 (d, J = 12.1Hz, 1H), 3.78 (s, 3H) ppm; High-resolution mass spectrometry: C₂₆H₁₆F₆N₄O₂ [M+H] + Calculated value: 531.12502, measured value: 531.12531.

[0372] Example 71

[0373]

[0374] Synthesize Example 71 (35 mg, 72% yield) according to the procedure of General Synthesis Method 1. 1 ¹H NMR (500MHz, CDCl₃) δ 9.11 (s, 1H), 8.30 (s, 1H), 8.12 (dd, J = 7.7, 1.8Hz, 1H), 8.05 (d, J = 1.0Hz, 1H), 7.89 (d, J = 0.9Hz, 1H), 7.82–7.76 (m, 4H), 7.55–7.52 (m, 1H), 7.49–7.45 (m, 1H), 7.44 (d, J = 8.0Hz, 1H) ppm; High-resolution mass spectrometry: C₂₃H₁₂F₃N₅O₂ [M+H] + Calculated value: 48.10169, measured value: 448.10172.

[0375] Example 72

[0376]

[0377] Example 72 (35 mg, 71% yield) was synthesized according to the procedure of General Synthesis Method 1. 1 H NMR (400MHz, CDCl3) δ9.01(s,1H),8.19(s,1H),8.03(dd,J=7.6,1.8Hz,1H),7.62(d,J=8.6Hz,2H),7.41(d d,J=7.3,1.7Hz,4H),7.36-7.33(m,1H),5.97(s,1H),2.29(s,3H),2.26(s,3H)ppm; Mass spectrum: C26H17F3N4O2[M+H] + Calculated value: 475.1, measured value: 475.1.

[0378] Example 73

[0379]

[0380] Example 73 (8 mg, 40% yield) was synthesized using the same procedure as Example 69. 1 H NMR(500MHz, CDCl3)δ8.99(s,1H),8.02–7.90(m,1H),7.77(s,1H),7.50–7.41(m,7H),6.94(d ,J=12.0Hz,1H),6.84(d,J=12.0Hz,1H),6.03(s,1H),2.33(s,6H)ppm; Mass spectrum: C26H19F3N4O2[M+H] + Calculated value: 477.2, measured value: 477.2.

[0381] Example 74

[0382]

[0383] Synthesize Example 74 (3 mg, 15% yield) according to the procedure of General Synthesis Method 1. 1 H NMR(500MHz, CDCl3)δ8.99(s,1H),8.04(dd,J=7.6,1.7Hz,1H),7.65(s,1H),7.54–7.49(m,1H),7.46(d,J=7.5Hz,1H),7.43(d,J=8.0Hz, 1H),7.34(d,J=8.2Hz,2H),7.25(s,2H),5.99(s,1H),3.17(dd,J=16.2,6.3Hz,4H),2.31(s,3H),2.28(s,3H)ppm; Mass spectrum: C26H21F3N4O2[M+H] + Calculated value: 479.2, measured value: 479.2.

[0384] Example 75

[0385]

[0386] Example 75 (11 mg, 29% yield) was synthesized according to the procedure of General Synthesis Method 3. Structural characterization: 1H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.21(s,1H),7.93-7.80(m,1H),7.68(q,J=8.1Hz,4H),7.40(t,J=8.1 Hz,1H),7.33(s,1H),7.09(dd,J=8.1,5.5Hz,2H),4.60(p,J=6.1Hz,1H),3.80(s,3H),1.32(d,J=6.0Hz,6H); Mass spectrum: C 28 H 22 F3N4OS[M+H] + Calculated value: 519.1, measured value: 519.2.

[0387] Example 76

[0388]

[0389] Example 76 (6 mg, 47% yield) was synthesized following the procedure outlined in General Synthesis Method 3. Structural characterization: 1 H NMR(500MHz,Chloroform-d)δ9.33(s,1H),7.78(dd,J=7.7,1.9Hz,1H),7.54(d,J=8.0Hz,2H),7.49(s,1H),7.40(td,J=7.8,1.9Hz,1H),7.31-7.2 7(m,3H),7.09(dd,J=8.1,5.2Hz,2H),4.56(p,J=6.1Hz,1H),3.75(s,3H) ,3.36(t,J=7.6Hz,2H),3.22(t,J=7.6Hz,2H),1.28(d,J=6.1Hz,6H); Mass spectrum: C 28 H 25 F3N4OSNa[M+Na] + Calculated value: 545.2, measured value: 545.3.

[0390] Example 77

[0391]

[0392] Intermediate A-5 (X = S, R2 = 2-isopropylphenyl, 100 mg, 0.26 mmol), (BPin)2 (134 mg, 2.0 eq), Pd(dppf)2Cl2 (10 mg, 0.05 eq), and AcOK (51 mg, 2.0 eq) were added sequentially to a 10 mL reaction tube, followed by 1 mL of 1,4-dioxane solvent. The reaction was carried out at 100 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and washed by silica gel column chromatography to obtain crude borate ester. Compound L-5, Pd(dppf)2Cl2, and K2CO3 were weighed and added sequentially to a reaction tube containing 25 mL of crude product. 1,4-dioxane / water (v / v, 5:1) was added, and the mixture was reacted at 90 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated to dryness, and purified by preparative silica gel thin-film chromatography to obtain the target product (Example 77, 5 mg, 6% yield). 1 ¹H NMR (400MHz, Chloroform-d) δ 9.36 (s, 1H), 7.72 (d, J = 7.7Hz, 1H), 7.62–7.51 (m, 3H), 7.45 (t, J = 11.1Hz, 3H), 7.31 (d, J = 6.6Hz, 3H), 4.37 (s, 2H), 3.75 (s, 3H), 3.66–3.54 (m, 1H), 1.26 (d, J = 5.3Hz, 6H); High-resolution mass spectrometry: C 27 H 23 F3N4SNa[M+Na] + Calculated value: 515.14932, measured value: 515.14880.

[0393] Example 78:

[0394]

[0395] Intermediate compounds A-5 (X = S, R2 = 2-isopropylphenyl, 40 mg, 0.1 mmol), L-6 (40 mg, 1.5 eq), Pd2(dba)3 (10 mg, 0.1 eq), XantPhos (12 mg, 0.2 eq), and Cs2CO3 (103 mg, 3.0 eq) were added sequentially to a 10 mL reaction tube. 0.5 mL of anhydrous 1,4-dioxane was added, and the mixture was purged three times with argon gas. The reaction was carried out overnight at 110 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the organic phase was evaporated to dryness. The product was purified twice by preparative thin-layer chromatography to obtain the target product in Example 78 (12 mg, 22% yield). Structural characterization: 1H NMR(400MHz,Chloroform-d)δ9.37(s,1H),7.74(s,1H),7.66(dd,J=7.5,1.2Hz,1H),7.50-7.44(m,2H),7.4 3-7.35(m,2H),7.26-7.22(m,2H),6.96-6.88(m,2H),3.71(s,3H),3.53(s,4H),1.13(d,J=6.9Hz,6H); Mass spectrum: C 27 H 25 F3N5S[M+H] + Calculated value: 508.2, measured value: 508.2.

[0396] Example 79

[0397]

[0398] Example 79 (30 mg, 57% yield) was synthesized using the procedure described in Example 78. Structural characterization: 1 H NMR(400MHz,Chloroform-d)δ9.33(s,1H),7.70(dd,J=7.7,1.4Hz,1H),7.65-7.59(m,2H),7.54-7.45(m,2H),7 .41(s,1H),7.33(d,J=4.3Hz,2H),7.31-7.28(m,2H),3.78(s,3H),3.53(p,J=6.8Hz,1H),1.30(d,J=6.8Hz,6H). Mass Spectrum:C 26 H 22 F3N5SNa[M+Na] + Calculated value: 516.1, measured value: 516.2.

[0399] Example 80

[0400]

[0401] Example 80 (9.0 mg, 20% yield) was synthesized using the procedure described in Example 78. ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, ¹H), 8.13 (dd, J = 7.5, 1.9 Hz, ¹H), 7.99 (s, ¹H), 7.86 (d, J = 0.7 Hz, ¹H), 7.75 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.52–7.41 (m, 3H), 6.33 (s, ¹H), 5.49–5.47 (m, 1H), 4.60 (d, J = 2.7 Hz, 2H). C₂₂H₁₅F₃N₆OSNa[M+Na]+ Calculated value: 491.1, measured value: 491.1.

[0402] Example 81

[0403]

[0404] Example 81 (5.1 mg, 22% yield) was synthesized using the procedure described in Example 78. 1 H NMR(300MHz, CDCl3)δ9.25(s,1H),7.69–7.57(m,3H),7.51(dd,J=10.1,4.8Hz,3H),7.48–7.40(m,2H),7.31(s,1H),6.32(s,1H), 5.42–5.40(m,1H),4.56(d,J=3.7Hz,2H),3.77(s,3H),3.48(dt,J=13.6,6.9Hz,1H),1.27(s,3H),1.24(s,3H).C27H25F3N5S[M+H] + Calculated value: 508.2, Actual measurement: 508.2.

[0405] Example 82

[0406]

[0407] Example 82 (13.1 mg, 25% yield) was synthesized using the procedure described in Example 78. 1 H NMR (400MHz, CDCl3) δ9.25(s,1H),7.68–7.62(m,1H),7.55(d,J=8.3Hz,2H),7.45(qd,J=8.0,4.5Hz,4H),7.31(td,J=7.6,1.5Hz,1H),6.46(s,1H ),6.32(s,1H),5.43–5.41(m,1H),4.57(d,J=4.8Hz,2H),3.49(dt,J=13. 7,6.8Hz,1H),2.35(s,3H),1.27(s,3H),1.26(s,3H).C27H25F3N5S[M+H] + Calculated value: 508.2, Actual measurement: 508.2.

[0408] Example 83

[0409]

[0410] Example 83 (12.1 mg, 26% yield) was synthesized using the procedure described in Example 78. 1H NMR(400MHz, CDCl3)δ9.27(s,1H),8.13(dd,J=7.6,1.9Hz,1H),7.55(t,J=5.8Hz,2H),7.52–7.39(m,5H ),6.46(s,1H),6.32(s,1H),5.47–5.45(m,1H),4.59(d,J=4.5Hz,2H),2.35(s,3H).C25H18F6N5OS[M+H] + Calculated value: 550.1, Measured value: 550.1.

[0411] Example 84

[0412]

[0413] Example 84 (7.2 mg, 24% yield) was synthesized using the procedure described in Example 78. 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),8.16–8.08(m,1H),7.63(d,J=8.1Hz,2H),7.55–7.48(m,3H),7.44(d,J=11.4Hz,1H ),7.31(s,1H),6.74(d,J=8.7Hz,1H),6.32(s,1H),5.35(s,1H),4.59–4.57(m,2H),3.77(s,3H).C25H18F6N5OS[M+H] + Calculated value: 550.1, Measured value: 550.1.

[0414] Example 85

[0415]

[0416] Example 85 (10.0 mg, 22% yield) was synthesized using the procedure described in Example 78. 1 H NMR(300MHz, CDCl3)δ9.25(s,1H),7.68–7.59(m,1H),7.54–7.52(m,4H),7.48–7.39(m,3H),7.32(dd,J=7.2,1.4Hz,1H),6.34(s,1H), 5.40(s,1H),4.57–4.55(m,3H),3.48(dt,J=13.7,6.8Hz,1H),1.46(s,3H),1.44(s,3H),1.26(s,3H),1.24(s,3H).C29H29F3N5S[M+H] + Calculated value: 536.2, Measured value: 536.2.

[0417] Example 86

[0418]

[0419] Example 86 (13.0 mg, 29% yield) was synthesized using the same procedure as Example 78. 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),8.12(dd,J=7.6,1.9Hz,1H),7.57–7.49(m,5H),7.47(dd,J=7.5,1.5Hz,1H),7.44 –7.40(m,2H),6.33(s,1H),5.45(t,J=5.3Hz,1H),4.64–4.52(m,3H),1.46(s,3H),1.45(s,3H).C27H22F6N5OS[M+H] + Calculated value: 578.1, Measured value: 578.1.

[0420] Example 87

[0421]

[0422] Example 87 (7.1 mg, 23% yield) was synthesized using the procedure described in Example 78. 1 H NMR (300MHz, CDCl3) δ9.27(s,1H),8.00(s,1H),7.86(s,1H),7.75(d,J=8.4Hz,2H),7.67(d,J=7.6Hz,1H),7.60(d,J=8.2Hz,2H),7.48(t,J=8.1Hz ,2H),7.33(d,J=7.8Hz,1H),6.34(s,1H),5.46(s,1H),4.60–4.58(m,2H) ,3.51(dt,J=13.6,6.9Hz,1H),1.28(s,3H),1.27(s,3H).C24H23N6S[M+H] + Calculated value: 427.2, Measured value: 427.2.

[0423] Example 88

[0424]

[0425] Example 88 (5.3 mg, yield 21%) was synthesized using the same procedure as Example 78. 1H NMR (500MHz, CDCl3) δ7.82 (dd, J=31.4, 6.4Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.6 0(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),7.43(d,J=7.7Hz,1H),7.40–7.36(m ,1H),7.30(s,1H),6.08(s,1H),5.42(s,1H),4.52–4.50(s,2H),3.75(s,3H), 3.67–3.59(m,1H),3.43(s,6H),1.27(s,3H),1.26(s,3H).C29H30F3N6S[M+H] + Calculated value: 551.2, Measured value: 551.2.

[0426] Example 89

[0427]

[0428] Example 89 was synthesized using the procedure of General Synthesis Method 3, with DME as the solvent (12 mg, yield 23%). 1 HNMR(400MHz,Chloroform-d)δ7.92(s,1H),7.79(dd,J=7.7,1.4Hz,1H),7.66-7.56(m,4H),7.47-7.42(m,1H),7.38(td,J=7.6,1 .4Hz,1H),7.30(s,1H),7.23(dd,J=7.5,1.3Hz,1H),5.35-5.23(m,1H),3.76(s,4H),3.22(d,J=4.8Hz,3H),1.32(d,J=6.9Hz,6H). Mass Spectrum:C 29 H 25 F3N5S[M+H] + Calculated value: 532.18, measured value: 532.1.

[0429] Example 90

[0430]

[0431] Example 90 (6 mg, yield 59%) was synthesized using the procedure described in General Synthesis Method 3. 1H NMR(400MHz,Chloroform-d)δ7.78(d,J=7.7Hz,1H),7.53(d,J=7.8Hz,2H),7.48(d,J=7.4Hz,1H),7.43(d,J=8.1Hz,1H),7.32-7 .28(m,4H),7.21(s,1H),5.07-4.92(m,1H),3.80-3.70(m,4H),3.31-3.23(m,5H),3.18(t,J=7.6Hz,2H),1.33(d,J=6.9Hz,6H). Mass Spectrum:C 29 H 29 F3N5S[M+H] + Calculated value: 536.21, measured value: 536.1.

[0432] Example 91

[0433]

[0434] Example 91 (3 mg, yield 41%) was synthesized using the procedure of General Synthesis Method 3. 1 H NMR(400MHz, CDCl3)δ8.07(s,1H),7.87(dd,J=7.7,1.2Hz,1H),7.71–7.60(m,4H),7.46(dtd,J=9.1,7.9, 1.3Hz,2H),7.31(ddd,J=8.6,5.4,1.5Hz,2H),4.23(s,3H),3.83–3.70(m,4H),1.36(s,3H),1.34(s,3H). Mass spectrum: C29H24F3N4OS[M+H] + Theoretical value 533.15, measured value 533.2.

[0435] Example 92

[0436]

[0437] Example 92 (6.7 mg, yield 76%) was synthesized using the procedure of General Synthesis Method 3. 1H NMR(400MHz, CDCl3)δ7.79(dd,J=7.7,1.3Hz,1H),7.54–7.47(m,3H),7.46–7.41(m,1H),7.36(s,1H),7.34–7.26(m,4H),4.2 0(s,3H),3.77–3.71(m,4H),3.30(t,J=7.6Hz,2H),3.16(t,J=7.6Hz,2H),1.33(s,3H),1.31(s,3H). Mass spectrum: C29H28F3N4OS[M+H] + Theoretical value 537.19, measured value 537.2.

[0438] Example 93

[0439]

[0440] Example 93 was synthesized following the procedure of General Synthesis Method 3. (3.1 mg, yield 42%) 1 H NMR (500MHz, CDCl3) δ8.17(s,1H),7.76(dd,J=7.7,1.3Hz,1H),7.71–7.68(m,2H),7.67–7.62(m,2H),7.48(dd,J=7.3,6.1Hz,1H),7.44(td,J=7.7,1. 4Hz,1H),7.31(ddd,J=8.7,5.8,1.2Hz,2H),3.80(s,3H),3.59(dt,J=13.6 ,6.8Hz,1H),2.89(s,3H),1.34(s,3H),1.33(s,3H). Mass spectrum: C29H24F3N4S[M+H] + Theoretical value 517.16, measured value 517.2.

[0441] Example 94

[0442]

[0443] Example 94 (3.1 mg, yield 42%) was synthesized using the procedure of General Synthesis Method 3. 1H NMR (400MHz, CDCl3) δ7.72(d,J=7.7Hz,1H),7.55(d,J=7.1Hz,3H),7.49(d,J=8.5Hz,3H),7.19(s,1H),7.02(s,2H),3.77(dd, J=8.0,3.8Hz,4H),3.33(d,J=8.1Hz,2H),3.20(d,J=8.6Hz,2H),2.87(s,3H),1.32(s,3H),1.30(s,3H). Mass spectrum: C29H28F3N4S[M+H] + Theoretical value 521.19, measured value 521.2.

[0444] Example 95

[0445]

[0446] Example 95 (20 mg, yield 29%) was synthesized according to the procedure of General Synthesis Method 1. 1 H NMR(400MHz,Chloroform-d)δ9.48(s,1H),8.72(s,1H),8.32(s,1H),7.74(d,J=8.4Hz,2H),7.69(d,J=8.4Hz, 2H), 7.37 (d, J = 1.3Hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 1.91-1.84 (m, 1H), 0.99-0.94 (m, 2H), 0.93-0.83 (m, 2H). Mass Spectrum:C 27 H 20 F3N6OS[M+H] + Calculated value: 533.1, measured value: 533.0.

[0447] Example 96

[0448]

[0449] Example 96 (4 mg, yield 23%) was synthesized according to the procedure of General Synthesis Method 1. 1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),8.71(s,1H),7.60(d,J=1.0Hz,1H),7.57-7.52(m,2H),7.33-7.29(m,2H),7.28(s,1H),3. 96(s,3H),3.77(s,3H),3.39-3.33(m,2H),3.21(t,J=7.6Hz,2H),1.83-1.77(m,1H),1.27(dd,J=4.2,2.3Hz,2H),0.93-0.90(m,2H). Mass Spectrum:C 27 H 24 F3N6OS[M+H] + Calculated value: 537.2, measured value: 537.1.

[0450] Example 97

[0451]

[0452] Example 97 (17 mg, yield 14%) was synthesized according to the procedure of General Synthesis Method 1. 1 ¹H NMR (500MHz, Chloroform-d) δ 9.46 (s, 1H), 8.69 (s, 1H), 8.30 (s, 1H), 7.76–7.70 (m, 2H), 7.51–7.44 (m, 2H), 6.49 (s, 1H), 3.95 (s, 3H), 2.39 (s, 3H), 1.87–1.82 (m, 1H), 0.95–0.91 (m, 2H), 0.90–0.84 (m, 2H). Mass spectrometry: C 27 H 20 F3N6OS[M+H] + Calculated value: 533.1, measured value: 533.1.

[0453] Example 98

[0454]

[0455] Example 98 (8 mg, yield 47%) was synthesized according to the procedure of General Synthesis Method 1. 1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),8.71(s,1H),7.63(s,1H),7.36(d,J=8.5Hz,2H),7.31(d,J=8.2Hz,2H),6.47(s, 1H),3.96(s,3H),3.36(t,J=7.6Hz,2H),3.22(t,J=7.1,2H),2.34(s,3H),1.8-1.77(m,1H),1.29-1.24(m,2H),0.92(m,2H). Mass Spectrum:C 27 H 24 F3N6OS[M+H] + Calculated value: 537.2, measured value: 537.2.

[0456] Example 99

[0457]

[0458] Example 99 (4.5 mg, yield 12%) was synthesized using the procedure described in Example 77. ¹H NMR (500 MHz, Chloroform-d) δ 9.42 (s, 1H), 8.69 (s, 1H), 7.59 (s, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.42 (s, 1H), 4.59–4.52 (m, 1H), 4.38 (s, 2H), 3.95 (s, 3H), 1.73 (dt, J = 8.2, 3.7 Hz, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.26–1.24 (m, 2H), 0.88–0.86 (m, 2H). Mass spectrometry: C 28 H 26 F3N6OS[M+H] + Calculated value: 551.2, measured value: 551.2.

[0459] Example 100

[0460]

[0461] Example 100 (6.0 mg, yield 18%) was synthesized using the procedure described in Example 77. 1¹H NMR (400MHz, Chloroform-d) δ 9.43 (s, 1H), 8.71 (s, 1H), 7.64–7.58 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 4.39 (s, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.77–1.71 (m, 1H), 1.28–1.24 (m, 2H), 0.91–0.87 (m, 2H). Mass spectrometry: C 26 H 22 F3N6OS[M+H] + Calculated value: 523.2, measured value: 523.1.

[0462] Example 101: Determination of the inhibition rate of 100 μM compound against USP1 / UAF1

[0463] The inhibition rate of the 100 μM compound on USP1 / UAF1 was evaluated by measuring the deubiquitinase activity of USP1 / UAF1 using Ub-AMC as a substrate. The principle of the assay is that USP1 / UAF1 cleaves the amide bond between the C-terminal glycine of AMC and ubiquitin, which increases the fluorescence signal.

[0464] The assay conditions were as follows: 70 μl of buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM DTT, 0.05% Tween 20) and 35 μl of a 500 μM small molecule compound solution (containing 5% DMSO) were added to 35 μl of a 2.5 nM USP1 / UAF1 enzyme solution. The mixture was gently mixed to obtain 140 μl of the final solution and incubated at the experimental temperature for 20 min. 40 μl of the final solution was then aspirated, and 10 μl of a 5 μM substrate solution was added to initiate the reaction. The solution was immediately placed in a microplate reader and the reaction was read kinetically at 25 °C under Ex360 / Em460 conditions, every 30 seconds for 10 minutes. The control group was replaced with 35 μl of buffer containing 5% DMSO without the compound. The relative activity percentage of USP1 / UAF1 was calculated from the data. The assay included one blank well and three sample wells.

[0465] The relative activity of USP1 / UAF1 at 100 μM compound was calculated using the following formula:

[0466] Note: cpd_Time 1 is the average reading at the start of the reaction in the experimental group, cpd_Time 2 is the average reading at 10 minutes of reaction in the experimental group, ctrl_Time 1 is the average reading at the start of the reaction in the 1% DMSO control group, and ctrl_Time 2 is the average reading at 10 minutes of reaction in the 1% DMSO control group.

[0467] The inhibition rate of the 100 μM compound against USP1 / UAF1 is:

[0468] Inhibition(%)=1-USP1 / UAF1 activity(%)

[0469] Reagents: Ub-AMC, Hefei KS-V Peptide Biotechnology Co., Ltd; 5M Nacl, SangoBiotech, B548121; 2M Tris-Hcl 7.5, Sango Biotech, Cat#B548139; 7.3μM USP1 / UAF1, R&D Systems.

[0470] Inhibition rates of certain compounds (100 μM) against the USP1 / UAF1 enzyme in this invention. Inhibition rates of the 100 μM concentration of the compound against the USP1 / UAF1 enzyme: “+” indicates inhibition rate ≤ 25%; “++” indicates 25% < inhibition rate ≤ 50%; “+++” indicates 50% < inhibition rate ≤ 75%; “++++” indicates 75% < inhibition rate ≤ 100%.

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] Example 102: Determination of the half-maximal inhibitory concentration (IC50) of the compound against the USP1 / UAF1 enzyme

[0488] The half-maximal inhibitory concentration (IC50) of the compound against USP1 / UAF1 50 The method for evaluating the value is as follows: The activity of USPl / UAF1 deubiquitinase is measured using Ub-AMC as a substrate. The principle of the assay is that USPl / UAF1 cleaves the amide bond between the C-terminal glycine of AMC and ubiquitin, which increases the fluorescence signal.

[0489] The assay conditions were as follows: 70 μl of buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM DTT, 0.05% Tween 20) and 35 μl of a series of small molecule compound solutions (containing 5% DMSO) of different concentrations (500 μM, 150 μM, 50 μM, 15 μM, 5 μM, 1.5 μM, 0.5 μM, 0.15 μM, 0.05 μM, 0.015 μM, 0.005 μM) were added to 35 μl of 2.5 nM USP1 / UAF1 enzyme solution. The mixture was gently mixed to 140 μl and incubated at the test temperature for 20 min. Take 40 μl of the mixture, add 10 μl of 5 μM substrate solution to initiate the reaction, and quickly place it in a microplate reader. Read the reaction in kinetic mode at 25°C under Ex360 / Em460 conditions, reading every 30 seconds for 10 minutes. The control group is replaced with 35 μl of compound-free buffer containing 5% DMSO. Calculate the relative activity percentage of USP1 / UAF1 from the data. The assay includes one blank well and three sample wells.

[0490] The relative activity of USP1 / UAF1 at different compound concentrations was calculated using the following formula:

[0491]

[0492] The activity data were analyzed and plotted using GraphPad Prism statistical software. An S-shaped dose-activity curve was plotted using a nonlinear regression model ([Inhibitor] vs. response - Variable slope four parameters), and the IC50 was calculated. 50 value.

[0493] Note: Among them, cpd_Time 1 is the average value of the starting reading of the reaction in the experimental group, cpd_Time 2 is the average value of the reading of the reaction in the experimental group at 10 min, ctrl_Time 1 is the average value of the starting reading of the 1% DMSO control group, and ctrl_Time 2 is the average value of the reading of the reaction in the 1% DMSO control group at 10 min.

[0494] Reagents: Ub-AMC, Hefei KS-V Peptide Biotechnology Co., Ltd; 5M Nacl, SangoBiotech, B548121; 2M Tris-Hcl 7.5, Sango Biotech, Cat#B548139; 7.3μM USP1 / UAF1, R&DSystems.

[0495] The half-maximal inhibitory concentration (IC50) of some compounds of the present invention against the USP1 / UAF1 enzyme. The half-maximal inhibitory concentration (IC50, μM) of the compound against the USP1 / UAF1 enzyme: "+" indicates IC50 > 10 μM; "++" indicates 1 μM < IC50 ≤ 10 μM; "+++" indicates 0.5 μM < IC50 ≤ 1 μM; "++++" indicates IC50 ≤ 0.5 μM.

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. The compound represented by general formula (I) or its salt: in, X is selected from: -S- or -O-; Y is selected from: -CH2-, where n is 0 or 1; R1is selected from: -H, -OR 1c or -CH2R 1d ; R 1c , R 1d are identical or different and independently of each other selected from the group consisting of: hydrogen or C1-C4 linear alkyl; R2is selected from: phenyl or pyrimidinyl, said phenyl or pyrimidinyl being substituted with substituents R 2a one or more times, the same or different; R 2a is selected from: hydrogen, C1-C4linear alkyl or alkoxy, C3-C4branched alkyl or alkoxy, C3-C4cyclic alkyl or alkoxy, haloC1-C4linear alkyl or alkoxy, haloC3-C4branched alkyl or alkoxy, or haloC3-C4cyclic alkyl or alkoxy; R3is selected from: phenyl, said phenyl being substituted with substituents R 3a one or more times, the same or different; R 3a is selected from: hydrogen, pyrazolyl, imidazolyl or triazolyl; which pyrazolyl, imidazolyl or triazolyl is substituted, one or more times, identically or differently, with a substituent R4; R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, or halo-C3-C4 branched alkyl.

2. The compound of claim 1 or a salt thereof: wherein: R 1c , R 1d are identical or different and independently of each other selected from the group consisting of hydrogen, methyl, ethyl or propyl.

3. The compound of claim 2 or a salt thereof: wherein: R1 is selected from: -H, -OCH3, or -CH3.

4. The compound or a salt thereof according to any one of claims 1 to 3: wherein: R 2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl or trichloromethoxy.

5. The compound of claim 4 or a salt thereof: wherein: R2 is selected from: isopropylphenyl, isopropoxyphenyl, methoxyphenyl, trifluoromethoxyphenyl, or cyclopropylmethoxypyrimidinyl.

6. The compound or a salt thereof as claimed in claim 1, 2, 3 or 5: wherein: R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trichloromethyl.

7. The compound of claim 4 or a salt thereof: wherein: R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trichloromethyl.

8. The compound of claim 6 or a salt thereof: wherein: R3 is selected from:

9. The compound of claim 7 or a salt thereof: wherein: R3 is selected from:

10. Compounds of general formula (I) or their salts: in, X is selected from: -S-; Y is selected from: -NR ya - and n is 0 or 1 ; R ya selected from: hydrogen or C1-C4 straight chain alkyl; R1is selected from: -H or -NR 1a R 1b ; R 1a , R 1b are identical or different and independently of each other selected from the group consisting of: hydrogen or C1-C4 linear alkyl; R2is selected from: phenyl, which phenyl is substituted with substituents R 2a one or more times, the same or different; R 2a selected from: hydrogen, C1-C4 straight chain alkyl or alkoxy or C3-C4 branched chain alkyl or alkoxy; R3is selected from: phenyl, said phenyl being substituted with substituents R 3a one or more times, the same or different; R 3a is selected from: hydrogen, pyrazolyl, imidazolyl or triazolyl; which pyrazolyl, imidazolyl or triazolyl is substituted, one or more times, identically or differently, with a substituent R4; R4 is selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched alkyl, halo-C1-C4 straight-chain alkyl, or halo-C3-C4 branched alkyl.

11. The compound of claim 10 or a salt thereof: wherein: R ya is selected from: hydrogen or methyl.

12. The compound or a salt thereof as claimed in claim 10 or 11: wherein: R 1a , R 1b are identical or different and independently of each other selected from the group consisting of hydrogen, methyl, ethyl or propyl.

13. The compound of claim 12 or a salt thereof: wherein: R1 is selected from: -H, -NHCH3, or -NCH3CH3.

14. The compound or a salt thereof as claimed in claim 10, 11 or 13: wherein: R 2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropyl.

15. The compound of claim 12 or a salt thereof: wherein: R 2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropyl.

16. The compound of claim 14 or a salt thereof: wherein: R2 is selected from: isopropylphenyl.

17. The compound of claim 15 or a salt thereof: wherein: R2 is selected from: isopropylphenyl.

18. The compound or a salt thereof as claimed in claim 10, 11, 13, 15, 16 or 17: wherein: R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trichloromethyl.

19. The compound of claim 12 or a salt thereof: wherein: R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trichloromethyl.

20. The compound of claim 14 or a salt thereof: wherein: R4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or trichloromethyl.

21. The compound of claim 18 or a salt thereof: wherein: R3 is selected from:

22. The compound or a salt thereof as claimed in claim 19 or 20: wherein: R3 is selected from:

23. A compound or its salt: wherein: The compound is selected from: or 24. A pharmaceutical composition comprising a compound or a salt thereof as described in any one of claims 1 to 23, and / or optionally a pharmaceutically acceptable carrier, excipient, or diluent.

25. Use of a compound or salt thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to claim 24, for the manufacture of a medicament for the treatment and / or prevention of a disease caused by ubiquitin-specific protease 1 (USP1) activity.

26. The use of claim 25, wherein, The disease is: a cancer or a disease or condition associated with DNA damage.

27. The use of claim 26, wherein, The cancer is a BRCA1 or BRCA2 mutation-associated cancer. The disease is: a cancer or a disease or condition associated with DNA damage. The cancer is a BRCA1 or BRCA2 mutation-associated cancer.

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