USP1 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphic substances, eutectic substances, hydrates, solvates, metabolites, prodrugs and deuterated compounds thereof. The invention also relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition to treatment and / or prevention of USP1 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a USP1 inhibitor and a preparation method and use thereof. Background Art

[0002] Ubiquitination is a common post-translational modification that can be deubiquitinated by deubiquitinating enzymes (DUBs) acting on ubiquitinated substrates to catalyze the removal of ubiquitin moieties. Ubiquitin-specific proteases (USPs) contain 58 family members and are the largest family of deubiquitinating enzymes. USPs can regulate a variety of important cellular functions in the tumor environment, such as cell cycle, DNA damage repair mechanism, chromatin remodeling and other signaling pathways.

[0003] USP1 belongs to the USPs family and is one of the most well-studied DUBs. USP1 is highly expressed in a variety of tumors and is also associated with poor prognosis and metastasis of some tumors. USP1 can form a complex with USP1-Associated Factor 1 (UAF1), thereby regulating two DNA damage repair pathways, namely, translesion synthesis (TLS) and interstrand cross-linking damage repair pathway (ICL), and can also affect cell differentiation, thereby affecting cancer progression; in the TLS pathway, USP1 regulates the recruitment and conversion of high-fidelity and low-fidelity TLS polymerases by regulating the deubiquitination of proliferating cell nuclear antigen (PCNA); in the ICL repair pathway, USP1 regulates the deubiquitination of FANCD2, directs to nuclear DNA damage sites, co-localizes with BRCA1 and RAD51, and interacts with downstream FA proteins. In addition, USP1 can also affect the ubiquitination of ID proteins (family of DNA-binding protein inhibitors) to regulate cell proliferation and differentiation. USP1 inhibition leads to blockage of the FA repair pathway and increased error-prone repair in the TLS pathway, resulting in increased SSB repair errors, replication fork collapse or premature arrest, and SSB forms DSBs during S phase replication.

[0004] Homologous recombination (HR) is an error-free repair pathway involved in repairing double-strand DNA breaks (DSBs). When BRCA1 / 2 and other factor mutations cause damage to the HR repair pathway, the DSBs generated after inhibiting USP1 can only be repaired through error-prone pathways such as NHEJ and MMEJ, which can easily cause abnormal mutations such as gene deletion or structural changes, and cannot be repaired in time and correctly, leading to cell cycle arrest and apoptosis. Studies have confirmed that USP1 is more highly expressed in BRCA1-deficient tumors than in wild-type cells, and knocking out or inhibiting USP1 can lead to unstable replication forks and reduced viability of BRCA1-deficient cells, indicating that inhibiting USP1 and HR pathway defects can form a synergistic lethal effect.

[0005] In summary, USP1 small molecule inhibitors are a potential therapy for treating HR pathway-deficient tumors and can provide a new therapeutic strategy for tumor treatment. Summary of the invention

[0006] The present invention also provides a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0007]

[0008] wherein X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5) or NR6; L is selected from C=O, C(R7)(R8), O, S or Se;

[0009] R6 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0010] R7 and R8 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0011] R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl or C 2-6 The 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Each alkynyl group is independently unsubstituted or substituted with one or more R a replace;

[0012] R1 is selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace;

[0013] Or R1 and R2 are combined with the atoms to which they are connected to form a phenyl group or a 5-6-membered heteroaryl group, wherein the 5-6-membered heteroaryl group contains 1-3 heteroatoms selected from N, O and S, and the phenyl group and the 5-6-membered heteroaryl group are each independently unsubstituted or substituted by one or more R a replace;

[0014] R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form a C 3-6 Cycloalkyl;

[0015] or R3 and R4, together with the atoms to which they are attached, form a 5-6 membered heterocycloalkenyl or C 5-6 The 5-6 membered heterocycloalkenyl contains 1-3 heteroatoms selected from Se, O and S, and the 5-6 membered heterocycloalkenyl, C 5-6 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R a replace;

[0016] Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R b replace;

[0017] B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R c replace;

[0018] Each R b and R care independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0019] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0020] or R 11 and R 12 The P to which they are connected together forms a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0021] or R 17 and R 18 The atoms to which they are attached together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0022] C is selected from -C(O)NR i R j , C 6-10aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 6-10 The aryl group, the 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group are each independently unsubstituted or substituted with one or more R d replace;

[0023] Each R d Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0024] Each R a are independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R e replace;

[0025] Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R f replace;

[0026] Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S;

[0027] Each R i , R j , R k Each independently selected from the same or different hydrogen or C 1-6 alkyl.

[0028] In a specific embodiment, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, X1 is selected from N, and X2 is selected from N.

[0029] In a specific embodiment, Selected from Selected from Selected from

[0030] In one embodiment, Ring A is selected from Ring A is selected from

[0031] In one embodiment, B is selected from

[0032] In one embodiment, C is selected from C is selected from

[0033] Preparation method: Method 1:

[0034]

[0035] Step 1: The compound represented by formula Ia-1 and the compound represented by formula Ia-2 are subjected to substitution reaction to obtain the compound represented by formula Ia-3;

[0036] Step 2: The compound represented by formula Ia-3 and the compound represented by formula Ia-4 or the compound represented by formula Ia-5 are subjected to Suzuki coupling to obtain the compound represented by formula I;

[0037] Wherein, X1, X2, L, R1, R4, R5, ring A, B, and C are as defined above.

[0038] Method 2:

[0039]

[0040] Step 1: The compound represented by formula Ib-1 and the compound represented by formula Ia-2 are subjected to substitution reaction to obtain the compound represented by formula Ib-2;

[0041] Step 2: The compound represented by Formula Ib-2 is reacted with the compound represented by Formula Ia-4 or the compound represented by Formula Ia-5 by Suzuki coupling to obtain the compound represented by Formula Ib;

[0042] Step 3: The compound represented by Formula Ib is subjected to a metal-catalyzed coupling reaction to obtain the compound represented by Formula I;

[0043] Wherein, X1, X2, L, R1, R4, R5, ring A, B, and C are as defined above.

[0044] The present invention also provides use of the compound of the aforementioned formula or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or the pharmaceutical composition in the preparation of USP1 inhibitors.

[0045] Beneficial effects of the present invention:

[0046] The compounds of the present invention have excellent USP1 inhibitory activity and can be used as drugs for preventing and / or improving and / or treating diseases associated with this activity. DETAILED DESCRIPTION

[0047]

[0048] Preparation of intermediate I-1

[0049]

[0050] Step 1: Synthesis of I-1-2

[0051] I-1-1 (4.0 g, 48.7 mmol) was dissolved in tetrahydrofuran (55 mL), and 60% NaH (2.2 g, 55.0 mmol) was added to the solution in batches at 0°C. After the addition was completed, the reaction was stirred at 25°C for 1 h. Isopropyl iodide (10.0 g, 58.8 mmol) was added, and the reaction was placed in a sealed tube and reacted at 100°C for 2 h. The reaction was monitored by LC-MS. The reaction was completed, cooled in an ice-water bath, quenched by adding water, extracted with ethyl acetate, washed with saturated brine, and concentrated under reduced pressure to obtain 5.0 g of yellow oil I-1-2. MS m / z (ESI): 125.10 [M+H] + .

[0052] Step 2: Synthesis of intermediate I-1

[0053] I-1-2 (5.0 g, 40.0 mmol) was dissolved in tetrahydrofuran (100 mL), and n-BuLi (80 mL, 80.0 mmol) was added at -78 °C, and the mixture was heated to room temperature and stirred for 1 h. The system was cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-diborane (7.4 g, 80.0 mmol) was added dropwise. After the addition was completed, the mixture was stirred for 1 h, and the mixture was heated to 25 °C and stirred for another 3 h. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was subjected to silica gel column chromatography (PE:EA=3:1) to obtain 4.7 g of yellow oily intermediate I-1. MS m / z(ESI):251.10[M+H] + .

[0054] Preparation of intermediate I-2

[0055]

[0056] Step 1: Synthesis of I-2-3

[0057] I-2-1 (9.0 g, 44.4 mmol) and I-2-2 (6.8 g, 44.4 mmol) were dissolved in hexafluoroisopropanol (70 mL), triethylamine (8.9 g, 87.9 mmol) was added dropwise at 0°C, and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (PE:EA=10:1) to obtain 9.2 g of white solid I-2-3. MS m / z (ESI): 285.08 [M+H] + .

[0058] Step 2: Synthesis of general intermediate I-2

[0059] I-2-3 (9.2 g, 32.4 mmol) was dissolved in THF (90 mL), and DIBAL-H (1 mol / L, 97.2 mL, 97.2 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was stirred at 20°C for 2 h. Water was slowly added to quench the reaction, and saturated aqueous ammonium chloride solution (100 mL) and EA (150 mL) were added to extract and separate the liquids. The organic phase was spin-dried, and the residue was chromatographed on a silica gel column (PE:EA=3:1) to obtain 8.2 g of the product, a white solid intermediate I-2. MS m / z (ESI): 257.08 [M+H] + .

[0060] Preparation of intermediate I-3

[0061]

[0062] Step 1: Synthesis of I-3-3

[0063] At room temperature, I-3-2 (9.9 g, 37.0 mmol) and sodium acetate (3.0 g, 37.0 mmol) were added to water, and the resulting mixture was stirred and heated at 100 ° C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (100 mL) solution containing I-3-1 (5.0 g, 30.5 mmol), and then ammonia water (35 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was added to water (100 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1–1:1) gave 5.0 g of white solid compound I-3-3. MS m / z(ESI):271.06[M+H] + .

[0064] Step 2: Synthesis of I-3-4

[0065] Compound I-3-3 (3.0 g, 11.0 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (60%, 0.67 g, 17.0 mmol) was added in batches at 0°C. The reaction solution was stirred at 0°C for 0.5 h, and then iodomethane (3.2 g, 22.0 mmol) was added, and the temperature was slowly restored to room temperature for 2 h. The reaction solution was added to ice water (30 mL), and extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.0 g of white solid compound I-3-4. MS m / z (ESI): 285.08 [M+H] + .

[0066] Step 3: Synthesis of intermediate I-3

[0067] Compound I-3-4 (3.0 g, 11.0 mmol) was added to tetrahydrofuran (60 mL), and lithium aluminum tetrahydride (1.3 g, 33.0 mmol) was added in batches at 0°C. The resulting mixture was stirred at 0°C for 1 h, and then slowly returned to room temperature for 1 h. Water (10 mL) and 15% NaOH aqueous solution (10 mL) and 30 mL of water were added to the reaction solution at 0°C. After stirring at room temperature for 1 hour, the resulting mixture was filtered through diatomaceous earth, and the filter cake was rinsed with dichloromethane. The resulting filtrates were combined and concentrated under reduced pressure to remove the solvent to obtain an oily compound intermediate I-3 (3.0 g). MS m / z (ESI): 257.08 [M+H] + .

[0068] Preparation of intermediate I-3-7

[0069]

[0070] Step 1: Synthesis of compound I-3-7

[0071] Compound I-3-4 (1.5 g, 5.28 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and lithium aluminum hydride (0.7 g, 15.83 mmol) was added under ice bath, and stirred at room temperature for 1 hour. 1 mL of water, 1 mL of 15% sodium hydroxide aqueous solution, and 3 mL of water were slowly added dropwise under ice bath. The obtained mixture was stirred at room temperature for 1 hour and filtered through diatomaceous earth. The filter cake was rinsed with dichloromethane. The obtained filtrates were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase medium pressure preparation (EA / PE=10-70%) to obtain 0.9 g of white solid compound I-3-7. MS m / z(ESI):259.09[M+H] + .

[0072] Preparation of intermediate I-4

[0073]

[0074] Step 1: Synthesis of intermediate I-4-1

[0075] I-3 (6.0 g, 23.4 mmol) was dissolved in ethyl acetate (100 mL), and Dess-Martin oxidant (9.9 g, 23.4 mmol) was added at room temperature, and stirred overnight at room temperature. 200 mL of water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was concentrated. The residue was chromatographed on a silica gel column (PE:EA=2:1) ​​to obtain 5.2 g of white solid intermediate I-4-1. MS m / z (ESI): 255.18 [M+H] + .

[0076] Step 2: Synthesis of intermediate I-4

[0077] Under nitrogen protection, I-4-1 (5.2 g, 20.5 mmol) was dissolved in tetrahydrofuran (100 mL), stirred and cooled in an ice bath, methylmagnesium bromide (6.82 mL, 20.5 mmol) was added, and stirred overnight in an ice bath. 200 mL of water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was concentrated. The residue was chromatographed on a silica gel column (PE:EA=1:1) to obtain 4.5 g of white solid intermediate I-4. MS m / z (ESI): 271.18 [M+H] + .

[0078] Preparation of intermediate I-5

[0079]

[0080] Step 1: Synthesis of compound I-5-2

[0081] Add I-5-1 (3.0 g, 9.4 mmol) and I-3 (2.2 g, 8.5 mmol) to a two-necked bottle, add dioxane (20 mL) to dissolve, cool to 0 ° C, add potassium tert-butoxide (4.2 g, 37.7 mmol), and stir at room temperature for 2 hours. Slowly pour the reaction solution into ice water (20 mL), stir for 2 minutes, extract with ethyl acetate (3*20 mL), combine the organic phases, add saturated brine (10 mL) for washing, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify it by reverse phase medium pressure preparation (ACN:H2O=65:35), and freeze-dry in vacuo to obtain 4.1 g of colorless oily product I-5-2. MS m / z (ESI): 538.20 [M+H] + .

[0082] Step 2: Synthesis of compound I-5-3

[0083] I-5-2 (1.0 g, 1.86 mmol), 1-d (396.9 mg, 2.05 mmol), sodium carbonate (394.3 mg, 3.72 mmol), XPhos Pd G3 (31.5 mg, 0.04 mmol) were dissolved in dioxane (21 mL) and water (7 mL), replaced with nitrogen three times, heated and stirred at 90 ° C for 4 h, and the reaction of the raw materials was completed by LC-MS monitoring. The mixture was cooled to room temperature, filtered and concentrated, and purified by reverse phase medium pressure preparation (ACN: H2O = 55: 45), and vacuum freeze-dried to obtain 890.0 mg of colorless oily compound I-5-3. MS m / z (ESI): 652.30 [M+H] + .

[0084] Step 3: Synthesis of Compound I-5

[0085] I-5-3 (350.0 mg, 0.54 mmol) was added to a two-necked bottle, and DMF (2 mL) was added to dissolve. N-bromosuccinimide (105.1 mg, 0.59 mmol) was added thereto under an ice bath, and then stirred at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction by LC-MS monitoring, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by reverse phase medium pressure preparation (acetonitrile: water = 55:45, acid method), and vacuum freeze-dried to obtain 245.0 mg of white solid crude I-5. MS m / z (ESI): 731.0 [M+H] + .

[0086] Preparation of intermediate I-6

[0087]

[0088] Step 1: Synthesis of compound I-6-2

[0089] At room temperature, I-3-2 (79.9 g, 295.6 mmol) and sodium acetate trihydrate (40.2 g, 295.6 mmol) were added to water (400 mL), and the resulting mixture was stirred and heated at 100 ° C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (400 mL) solution containing I-6-1 (50.0 g, 246.3 mmol), and then ammonia water (250 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was added to water (300 mL), extracted with ethyl acetate (3*300 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=10:1–3:1) gave 68.0 g of compound I-6-2. MS m / z(ESI):309.1[M+H] + .

[0090] Step 2: Synthesis of compound I-6

[0091] Compound I-6-2 (25.0 g, 80.9 mmol) was dissolved in N, N-dimethylformamide (400 mL), potassium carbonate (16.8 g, 121.3 mmol) and iodomethane (7.6 mL, 121.3 mmol) were added. Stir overnight at room temperature. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (2*200 mL). The organic phases were combined and washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 15.4 g of compound I-6 was obtained by purification by silica gel column chromatography (PE:EA=20:1–8:1). MS m / z(ESI):322.8[M+H] + .

[0092] Preparation of compound 1

[0093]

[0094] Step 1: Synthesis of compound 1-c

[0095] I-2 (150.0 mg, 0.59 mmol) was added to a two-necked bottle, tetrahydrofuran (5 mL) was added to dissolve, and then the temperature was lowered to 0°C. Sodium hydride (21.2 mg, 0.88 mmol) was added thereto under nitrogen protection, and the mixture was stirred for 40 minutes under an ice bath. 1-a (143.1 mg, 0.88 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (10 mL), stirred for 2 minutes, and extracted with ethyl acetate (3*10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to finally obtain 130.0 mg of white solid 1-c. MS m / z (ESI): 383.08 [M+H] + .

[0096] Step 2: Synthesis of compound 1

[0097] 1-c (30.0 mg, 0.08 mmol), 1-d (76.0 mg, 0.39 mmol), potassium carbonate (54.2 mg, 0.39 mmol), Pd (DPPF) Cl2 (64.2 mg, 0.08 mmol) were dissolved in dioxane (8 mL) and water (2 mL), and the atmosphere was replaced with nitrogen. Stirred at 100 ° C for 4 h, and the reaction of the raw materials was completed by LC-MS monitoring. The mixture was cooled to room temperature, filtered and concentrated, and purified by reverse phase medium pressure preparation (ACN: H2O = 3: 2), and vacuum freeze-dried to obtain 11.0 mg of white solid compound 1. MS m / z (ESI): 497.18 [M+H] + .

[0098] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.56(d,J=1.0Hz,1H),7.65(d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),6.76(s, 1H),5.54(s,2H),3.84(s,3H),2.35(s,3H),2.24(s,3H),1.70-1.66(m,1H),1.04-0.98(m,2H),0.90-0.82(m,2H).

[0099] The compounds in the following table were prepared by referring to the method of compound 1

[0100]

[0101]

[0102]

[0103] Preparation of compound 6

[0104]

[0105] Step 1: Synthesis of compound 6-b

[0106] Add 6-a (1g, 5.29mmol) to a single-mouth bottle, add tetrahydrofuran (20mL) to dissolve, then add DHP (0.9g, 10.58mmol), PPTS (0.7g, 2.65mmol), stir overnight at 60°C, add 100mL of water to the reaction solution, extract the aqueous phase with ethyl acetate (3*20mL), combine the organic phases, add saturated brine (10mL) to wash, then dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is chromatographed on a silica gel column (PE:EA=4:1) to obtain 1.2g of white solid 6-b. MS m / z(ESI):273.05[M+H] + .

[0107] Step 2: Synthesis of compound 6-c

[0108] I-3 (112.6 mg, 0.44 mmol) was added to a two-necked bottle, DMF (5 mL) was added to dissolve, and then the temperature was lowered to 0°C. Sodium hydride (10.5 mg, 0.44 mmol) was added under nitrogen protection, and the mixture was stirred in an ice-water bath for 40 minutes. 6-b (120.0 mg, 0.44 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (50 mL), stirred for 2 minutes, and extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 130.0 mg of white solid 6-c. MS m / z (ESI): 493.38 [M+H] + .

[0109] Step 3: Synthesis of compound 6-d

[0110] Referring to the synthesis of compound 1, 1-c was replaced by 6-c. MS m / z (ESI): 607.28 [M+H] + .

[0111] Step 4: Synthesis of compound 6

[0112] 6-d (30.0 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction of the raw material was completed under LC-MS monitoring, and the mixture was concentrated and purified by reverse phase medium pressure preparation (ACN:H2O=3:2), and vacuum freeze-dried to obtain 2.0 mg of white solid compound 6. MS m / z (ESI): 523.18 [M+H]+ .

[0113] 1 H NMR (400MHz, DMSO-d6) δ14.14(s,1H),8.72(s,1H),8.37(s,1H),7.97(s,1H),7.78(d,J=8.2Hz,2H),7.68(d,J =8.2Hz,2H),5.73(s,2H),3.89(s,3H),3.82(s,3H),1.85-1.73(m,1H),1.11-1.03(m,2H),0.95-0.85(m,2H).

[0114] Preparation of compound 11

[0115]

[0116] Step 1: Synthesis of compound 11

[0117] 10 (20.0 mg, 0.04 mmol) was added to a two-necked flask, and DMF (5 mL) was added to dissolve and then cooled to 0°C. Under nitrogen protection, sodium hydride (3.2 mg, 0.08 mmol) was added thereto, and stirred for 40 minutes in an ice bath. Methyl iodide (10.8 mg, 0.06 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (5 mL), stirred for 2 minutes, and extracted with ethyl acetate (3*10 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by reverse phase medium pressure preparation (ACN:H2O=3:2), and lyophilized in vacuo to obtain 5.0 mg of white solid compound 11. MS m / z (ESI): 536.19 [M+H] + .

[0118] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),7.94(d,J=1.4Hz,1H),7.76(d,J=1.8Hz,1H),7.73(d,J=3.6Hz,2H),7.67(d,J=8.2Hz,2H),6. 57(d,J=3.2Hz,1H),5.64(s,2H),4.08(s,3H),3.83(s,3H),3.79(s,3H),1.70-1.60(s,1H),1.07-0.99(m,2H),0.87-0.79(m,2H).

[0119] Preparation of compound 14

[0120]

[0121] Step 1: Synthesis of compound 14

[0122] Compound 7 (32.0 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), N-chlorosuccinimide (9.0 mg, 0.07 mmol) was added, and the mixture was stirred at 60°C overnight. 5 mL of water was added, and the mixture was extracted with ethyl acetate (2*5 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was first purified by normal phase medium pressure preparation (EA / PE=10-70%), and then purified by reverse phase medium pressure preparation (ACN / H2O=5-65%), and lyophilized to obtain 11.0 mg of white solid compound 14. MS m / z (ESI): 556.14 [M+H] + .

[0123] 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.67(s,1H),7.95-7.91(m,1H),7.78-7.72(m,2H),7.68-7.62(m ,3H),5.67(s,2H),3.85(s,3H),3.79(s,3H),1.80-1.68(m,1H),1.07-0.97(m,2H),0.89-0.81(m,2H).

[0124] Preparation of compound 15

[0125]

[0126] Step 1: Synthesis of compound 15-a

[0127] Under nitrogen protection, compound 7 (200.0 mg, 0.38 mmol) was dissolved in N, N-dimethylformamide (8 mL), N-iodosuccinimide (94.9 mg, 0.42 mmol) was added under ice bath, stirred at room temperature for 3 hours, 10 mL of water was added, extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase medium pressure preparation (EA / PE=5-70%) to obtain 201.0 mg of light yellow solid 15-a. MS m / z (ESI): 648.08 [M+H] + .

[0128] Step 2: Synthesis of compound 15

[0129] Dissolve 15-a (40.0 mg, 0.06 mmol) in dioxane (5 mL), add tris(dibenzylideneacetone)dipalladium (22.6 mg, 0.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene (13.7 mg, 0.02 mmol), cuprous cyanide (83.0 mg, 0.93 mmol), replace with nitrogen, and stir at 100°C overnight. Filter, concentrate the filtrate under reduced pressure to obtain a crude product, which is first purified by normal phase medium pressure preparation (EA / PE=5-70%), and then purified by reverse phase medium pressure preparation (ACN / H2O=5-60%), and freeze-dried to obtain 2.8 mg of white solid compound 15. MS m / z (ESI): 547.17 [M+H] + .

[0130] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.33(s,1H),7.93(s,1H),7.74(d,J=8.0Hz,2H),7.66(d,J=7.8Hz ,2H),5.69(s,2H),3.84(s,3H),3.79(s,3H),1.79-1.69(m,1H),1.08-0.95(m,2H),0.90-0.76(m,2H).

[0131] Preparation of compound 16

[0132]

[0133] Step 1: Synthesis of compound 16

[0134] 10 (20.0 mg, 0.04 mmol) was added to a two-necked flask, acetonitrile (2 mL) was added to dissolve, and the temperature was lowered to 0°C. N-chlorosuccinimide (8.4 mg, 0.06 mmol) was added thereto under nitrogen protection, and the mixture was heated and stirred at 70°C overnight. The reaction of the raw material was monitored by LC-MS. The reaction solution was slowly poured into water (5 mL), extracted with ethyl acetate (3*5 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by reverse phase medium pressure preparation (ACN:H2O=1:1), and finally concentrated to obtain 12.0 mg of white solid 16. MS m / z (ESI): 556.14 [M+H] + .

[0135] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.98(s,1H),7.96(d,J=1.4Hz,1H),7.77(d,J=8.2Hz,2H),7.70(d,J=8 .2Hz,2H),5.70(s,2H),3.87(s,3H),3.80(s,3H),1.70-1.62(m,1H),1.09-1.01(m,2H),0.89-0.81(m,2H).

[0136] Preparation of compound 17

[0137]

[0138] Step 1: Synthesis of compound 17

[0139] Under nitrogen protection, compound 15-a (140.0 mg, 0.22 mmol) was dissolved in dioxane (6 mL), water (2 mL), trimethylcyclotriboroxane (50% tetrahydrofuran solution) (162.8 mg, 1.30 mmol), potassium carbonate (89.7 mg, 0.65 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichlorochloride complex (17.7 mg, 0.02 mmol), and stirred at 100°C overnight. Extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was first purified by normal phase medium pressure preparation (EA / PE=5-70%), and then purified by preparation and lyophilized to obtain 7.2 mg of light gray solid compound 17. MS m / z (ESI): 536.19 [M+H] + .

[0140] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.65(s,1H),7.93(d,J=0.8Hz,1H),7.74(d,J=8.2Hz,2H),7.63(d,J=8.2Hz,2H),7 .18(s,1H),5.62(s,2H),3.84(s,3H),3.79(s,3H),2.41(s,3H),1.78-1.69(m,1H),1.07-0.98(m,2H),0.88-0.79(m,2H).

[0141] Preparation of compound 18

[0142]

[0143] Step 1: Synthesis of compound 18

[0144] Under nitrogen protection, compound 7 (150.0 mg, 0.29 mmol) was dissolved in acetonitrile (8 mL) and pyridine (2 mL), and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo 2.2.2 octane bis(tetrafluoroborate) salt (152.9 mg, 0.43 mmol) was added under ice bath, and stirred at room temperature overnight. 10 mL of water was added, extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was first purified by normal phase medium pressure preparation (EA / PE=5-70%), and then purified by preparation, and then freeze-dried to obtain 16.0 mg of light gray solid compound 18. MS m / z (ESI): 540.17 [M+H] + .

[0145] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.66(s,1H),7.94(d,J=0.8Hz,1H),7.74(d,J=8.2Hz,2H),7.62(d,J=8.2Hz,2H), 7.43(t,J=2.4Hz,1H),5.66(s,2H),3.85(s,3H),3.79(s,3H),1.79-1.70(m,1H),1.06-0.99(m,2H),0.88-0.81(m,2H).

[0146] Preparation of compound 19

[0147]

[0148] Step 1: Synthesis of compound 19

[0149] Compound 10 (20.0 mg, 0.04 mmol) was dissolved in nitromethane (2 mL), and a selective fluorine reagent (5.0 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 16 h, and the reaction of the raw material was completed by LC-MS monitoring. The mixture was filtered and concentrated, and purified by reverse phase medium pressure preparation (ACN:H2O=3:2), and then lyophilized in vacuo to obtain 5.0 mg of white solid compound 19. MS m / z (ESI): 540.16 [M+H] + .

[0150] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),7.94(s,1H),7.82(d,J=2.4Hz,1H),7.75(d,J=8.2Hz,2H),7.68(d,J=8 .2Hz,2H),5.67(s,2H),3.85(s,3H),3.78(s,3H),1.72-1.65(m,1H),1.07-1.00(m,2H),0.90-0.82(m,2H).

[0151] Preparation of compound 20

[0152]

[0153] Step 1: Synthesis of compound 20-b

[0154] Referring to the synthesis of compound 1-c, 1-a was replaced by 20-a, and I-2 was replaced by I-3. MS m / z (ESI): 409.07 [M+H] + .

[0155] Step 2: Synthesis of compound 20-c

[0156] Compound 20-b (400.0 mg, 0.98 mmol), 3,4-dihydro-2H-pyran (164.6 mg, 1.96 mmol), 4-methylbenzenesulfonic acid pyridine (36.9 mg, 0.15 mmol) were dissolved in THF (15 mL) and stirred at 40°C overnight. 10 mL of water was added, extracted with ethyl acetate (2*15 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase medium pressure preparation (MeOH / DCM=0-10%) to obtain 418.0 mg of white solid compound 20-c. MS m / z (ESI): 493.13 [M+H] + .

[0157] Step 3: Synthesis of compound 20-d

[0158] Compound 20-c (100.0 mg, 0.20 mmol) was dissolved in dioxane (6 mL) and water (2 mL), and 1-d (47.2 mg, 0.24 mmol), XPhos Pd G3 (8.6 mg, 0.01 mmol), and potassium carbonate (84.1 mg, 0.61 mmol) were added. The mixture was replaced with nitrogen and reacted at 90 °C for 1.5 hours. The mixture was extracted with ethyl acetate (2*15 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase medium pressure preparation (EA / PE=10-80%) to obtain 64.0 mg of compound 20-d. MS m / z(ESI):607.23[M+H] + .

[0159] Step 4: Synthesis of compound 20

[0160] Compound 20-d (64.0 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative method and freeze-dried to obtain 7.8 mg of white solid compound 20. MS m / z (ESI): 523.17 [M+H] + .

[0161] 1 H NMR (400MHz, DMSO-d6) δ13.53(s,1H),8.68(s,1H),8.44(s,1H),7.94(d,J=1.0Hz,1H),7.74(d,J=7.8Hz,2H),7.65 (d,J=7.8Hz,2H),5.68(s,2H),3.85(s,3H),3.79(s,3H),1.79-1.68(m,1H),1.07-0.99(m,2H),0.90-0.80(m,2H).

[0162] Preparation of compound 21

[0163]

[0164] Step 1: Synthesis of compound 21-a

[0165] Add 10-a (188.0 mg, 1.0 mmol) to a single-mouth bottle, add DMF (5 mL) to dissolve, then add potassium carbonate (276 mg, 2 mmol), iodomethane (0.1 mL, 1.2 mmol), stir at room temperature for 2 hours, add 100 mL of water to the reaction solution, extract the aqueous phase with ethyl acetate (3*20 mL), combine the organic phases, add saturated brine (10 mL) to wash, then dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 180.0 mg of white solid 21-a. MS m / z (ESI): 202.09 [M+H] + .

[0166] Step 2: Synthesis of compound 21-b

[0167] Referring to the synthesis of compound 1-c, 1-a was replaced by 21-a, and I-2 was replaced by I-4. MS m / z (ESI): 607.28 [M+H] + .

[0168] Step 3: Synthesis of compound 21

[0169] Referring to the synthesis of compound 1, 1-c was replaced by 21-b. MS m / z (ESI): 550.20 [M+H] + .

[0170] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.94(d,J=0.8Hz,1H),7.76-7.72(m,3H),7.66(d,J=8.2Hz,2H),6.56(d,J=3.0Hz,1H),6.50(q ,J=6.4Hz,1H),4.15(s,3H),3.79(d,J=0.8Hz,6H),1.73(d,J=6.6Hz,3H),1.64-1.53(m,1H),1.04-0.93(m,2H),0.87-0.69(m,2H).

[0171] Preparation of compound 22

[0172]

[0173] Step 1: Synthesis of compound 22-b

[0174] Over a period of 30 minutes, fuming sulfuric acid (9.8 mL, 104.90 mmol) was slowly added dropwise to fuming nitric acid (1.26 mL, 29.97 mmol) at 0 ° C. Then 22-a (2.1 g, 14.98 mmol) was added in batches, keeping the internal temperature below 60 ° C. The reaction mixture was stirred at 80 ° C under nitrogen for 4 h and then cooled to room temperature. The reaction mixture was poured into ice. Once the ice melted, the reaction mixture was extracted with EA (3*50 mL). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the expected compound, which was 2.7 g of white solid 22-b. MS m / z(ESI):172.03[M+H] + .

[0175] Step 2: Synthesis of compound 22-c

[0176] To a solution of 22-b (1.1 g, 5.84 mmol) in anhydrous dichloromethane (25 mL) and DMF (0.5 mL) was added oxalyl chloride (0.74 mL, 8.77 mmol) dropwise over 10 minutes. The reaction mixture was stirred at 80 °C for 2 h. Concentration under reduced pressure gave 1.0 g of 22-c as a white solid. MS m / z (ESI): 189.99 [M+H] + .

[0177] Step 3: Synthesis of compound 22-d

[0178] 22-c was dissolved in anhydrous THF (20 mL) and acetone (10 mL), concentrated aqueous ammonium hydroxide solution (5.0 mL, 128.4 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 780.0 mg of 22-d as a white solid. MS m / z(ESI):171.04[M+H] + .

[0179] Step 4: Synthesis of compound 22-e

[0180] To a solution of 22-d (780.0 mg, 3.96 mmol) in anhydrous ethanol (50 mL) and ethyl acetate (50 mL) was added Raney Ni (80.0 mg). The reaction mixture was evacuated in vacuo and purged with hydrogen, then stirred at room temperature for 1 h. The reaction mixture was then filtered through a celite pad. The filtrate was concentrated in vacuo to give 597.0 mg of a brown solid 22-e. MS m / z (ESI): 141.04 [M+H] + .

[0181] Step 5: Synthesis of compound 22-f

[0182] Dissolve 22-e (597.0 mg, 4.26 mmol) in ACN (10 mL), add CDI (639.0 mg, 6.39 mmol), replace N2 protection. Heat and stir at 100°C overnight, and LC-MS monitors the completion of the reaction of the raw material. Filter the reaction solution to obtain 520.0 mg of brown solid 22-f. MS m / z (ESI): 167.04 [M+H] + .

[0183] Step 6: Synthesis of compound 22-g

[0184] 22-f (520.0 mg, 3.11 mmol) was dissolved in phosphorus oxychloride (4.47 mL, 48.16 mmol), and DBU (4.32 mL, 28.90 mmol) was added under ice bath, and nitrogen protection was replaced. The mixture was heated and stirred at 85°C overnight. LC-MS showed that the reaction of the raw material was complete, and the mixture was cooled to room temperature. The reaction solution was poured into ice water, and EA (2*20 mL) was added to extract twice, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was purified by normal phase medium pressure preparation (PE: EA = 5: 1), and concentrated under reduced pressure to obtain 310.0 mg of white solid product 22-g. MS m / z (ESI): 202.98 [M+H] + .

[0185] Step 7: Synthesis of compound 22-h

[0186] Referring to the synthesis of compound 1-c, 1-a was replaced by 22-g, and I-2 was replaced by I-3. MS m / z (ESI): 423.06 [M+H] + .

[0187] Step 8: Synthesis of compound 22

[0188] Referring to the synthesis of compound 1, 1-c was replaced by 22-h. MS m / z (ESI): 537.16 [M+H] + .

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.32(s,1H),7.95(d,J=1.4Hz,1H),7.77(d,J=8.4Hz,2H),7.70(d,J=8.4Hz, 2H),5.71(s,2H),4.29(s,3H),3.84(s,3H),3.80(s,3H),1.75-1.68(m,1H),1.07-0.98(m,2H),0.92-0.80(m,2H).

[0190] Preparation of compound 23

[0191]

[0192] Step 1: Synthesis of compound 23-b

[0193] At room temperature, I-3-2 (12.4 g, 46.1 mmol) and sodium acetate (3.8 g, 46.1 mmol) were added to water (120 mL), and the resulting mixture was stirred at 100 ° C for 1 hour. The reaction solution was cooled to room temperature, and then a solution of 23-a (7.0 g, 38.4 mmol) in methanol (80 mL) was added to the above mixture, and ammonia (30 mL) was added and stirred at room temperature overnight. Saturated brine (100 mL) was added, extracted with ethyl acetate (2*150 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE: EA = 10: 1-2: 1) to obtain 4.2 g of light yellow solid compound 23-b. MSm / z (ESI): 289.05 [M+H] + .

[0194] Step 2: Synthesis of compound 23-c

[0195] Dissolve 23-b (4.2 g, 10.9 mmol) in N,N-dimethylformamide (100 mL). Under nitrogen protection, add sodium hydride (0.9 g, 21.9 mmol) in an ice bath. After stirring for half an hour in an ice bath, add iodomethane (2.0 mL, 32.8 mmol) and stir at room temperature for 2 hours. Pour the reaction solution slowly into ice water, extract with ethyl acetate (2*80 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 4.1 g of light yellow solid compound 23-c. MS m / z (ESI): 303.07 [M+H] + .

[0196] Step 3: Synthesis of compound 23-d

[0197] Dissolve 23-c (4.1 g, 14.2 mmol) in a mixed solvent of tetrahydrofuran (30 mL) and methanol (15 mL). Add sodium borohydride (1.6 g, 42.7 mmol) and stir at room temperature overnight. Slowly add water to quench, extract with ethyl acetate (2*20 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (PE:EA=10:1-1:1) to obtain 3.0 g of yellow solid compound 23-d. MS m / z(ESI):275.07[M+H] + .

[0198] Step 4: Synthesis of compound 23-e

[0199] Referring to the synthesis of compound 1-c, 1-a was replaced by 21-a, and I-2 was replaced by 23-d. MS m / z (ESI): 440.08 [M+H] + .

[0200] Step 5: Synthesis of compound 23

[0201] Referring to the synthesis of compound 1, 1-c was replaced by 23-e. MS m / z (ESI): 554.18 [M+H] + .

[0202] 1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.98(s,1H),7.79-0.70(m,2H),7.68 -7.57(m,2H),6.58(d,J=2.8Hz,1H),5.68(s,2H),4.04(s,3H),3.82(s,3 H),3.80(s,3H),1.72-1.61(m,1H),1.06-0.98(m,2H),0.88-0.78(m,2H).

[0203] Preparation of compound 25

[0204]

[0205] Step 1: Synthesis of compound 25-b

[0206] At room temperature, I-3-2 (33.3 g, 123.5 mmol) and sodium acetate (10.1 g, 123.5 mmol) were added to water, and the resulting mixture was stirred and heated at 100 ° C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (200 mL) solution containing 25-a (15.0 g, 82.3 mmol), and then ammonia water (70 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was added to water (200 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1) gave 11.0 g of white solid compound 25-b. MS m / z(ESI):289.12[M+H] + .

[0207] Step 2: Synthesis of compound 25-c

[0208] Add 25-b (11.0 g, 38.2 mmol) to a two-necked bottle, add DMF (200 mL) to dissolve, cool to 0°C, add potassium carbonate (10.5 g, 76.4 mmol) under nitrogen protection, stir in an ice-water bath for 40 minutes, add iodomethane (6.5 g, 45.8 mmol) at 0°C, then stir at room temperature for 2 hours, slowly pour the reaction solution into ice water (500 mL), stir for 2 minutes, extract with ethyl acetate (3*50 mL), combine the organic phases, add saturated brine (100 mL) for washing, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is chromatographed on a silica gel column (PE:EA=5:1) to obtain 11.0 g of white solid 25-c. MS m / z(ESI):302.99[M+H] + .

[0209] Step 3: Synthesis of compound 25-d

[0210] 25-c (11.0 g, 36.4 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (50 mL). Stirring and cooling in an ice-water bath, sodium borohydride (2.8 g, 72.8 mmol) was added at 0°C, and the reaction was naturally heated to room temperature and stirred overnight. LC-MS monitored the completion of the reaction of the raw material, cooled to room temperature, filtered and concentrated, and purified by silica gel column chromatography (PE:EA=5:1) to obtain 11.0 g of white solid compound 25-d. MS m / z(ESI):275.12[M+H] + .

[0211] Step 4: Synthesis of compound 25-e

[0212] Referring to the synthesis of compound 1-c, 1-a was replaced by 21-a, and I-2 was replaced by 25-d. MS m / z (ESI): 440.14 [M+H] + .

[0213] Step 5: Synthesis of compound 25

[0214] Referring to the synthesis of compound 1, 1-c was replaced by 25-e. MS m / z (ESI): 554.20 [M+H] + .

[0215] 1H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.03(s,1H),7.77(d,J=3.0Hz,1H),7.63(dd,J=17.2,9.6Hz,2H),7.55(d,J=7.8Hz,1H),6.6 0(d,J=3.0Hz,1H),5.68(s,2H),4.11(s,3H),3.84(s,3H),3.63(s,3H),1.79-1.62(m,1H),1.10-0.95(m,2H),0.93-0.75(m,2H).

[0216] Preparation of compound 26

[0217]

[0218] Step 1: Synthesis of compound 26

[0219] Referring to the synthesis of compound 1, 1-c was replaced by 3-b, and 1-d was replaced by 24-b. MS m / z (ESI): 503.16 [M+H] + .

[0220] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.38(s,1H),7.96(s,1H),7.76(d,J=8.2Hz ,2H),7.62(d,J=8.2Hz,2H),5.49(s,2H),3.95(s,3H),3.89(s,6H),3.81(s,3H).

[0221] Preparation of compound 29

[0222]

[0223] Step 1: Synthesis of compound 29-b

[0224] I-5 (70.0 mg, 0.1 mmol), 29-a (0.8 mL), bis(triphenylphosphine)palladium dichloride (13.4 mg, 0.02 mmol), cuprous iodide (12.2 mg, 0.04 mmol) and TEA (2 mL) were added to a two-necked bottle. The atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C overnight. After the reaction was completed, the reaction solution was slowly poured into ice water (20 mL) and stirred for 2 minutes. It was extracted with ethyl acetate (3*20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase medium pressure preparation (ACN:H2O=65:35), and lyophilized in vacuo to obtain 40.0 mg of yellow solid 29-b. MSm / z(ESI):748.40[M+H] + .

[0225] Step 2: Synthesis of compound 29-c

[0226] 29-b (40.0 mg, 0.05 mmol) and potassium carbonate (22.2 mg, 0.16 mmol) were added to a two-necked bottle, and methanol (2 mL) was added and stirred at room temperature for 20 min. After the reaction was completed, water was added to quench the reaction as monitored by LC-MS, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by reverse phase medium pressure preparation (ACN:H2O=55:45), and lyophilized in vacuo to obtain 50.0 mg of yellow oily crude product 29-c. MS m / z (ESI): 676.30 [M+H] + .

[0227] Step 3: Synthesis of compound 29

[0228] 29-c (50.0 mg, 0.07 mmol) was added to a single-mouth bottle, DCM (5 mL) was added to dissolve, trifluoroacetic acid (2 mL) and water (0.01 mL) were added, and then stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction by LC-MS monitoring, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by reverse phase medium pressure preparation (acetonitrile: water = 55:45, acid method), and vacuum freeze-dried to obtain 8.0 mg of white solid compound 29. MS m / z (ESI): 564.20 [M+H] + .

[0229] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.36(s,1H),7.96(d,J=1.4Hz,1H),7.81-7.76(m,4H),7.68-7.54(m,1H) ,5.67(s,2H),3.87(s,3H),3.81(s,3H),2.57(s,3H),1.80-1.76(m,1H),1.08-1.05(m,2H),0.94-0.85(m,2H).

[0230] Preparation of compound 32

[0231]

[0232] Step 1: Synthesis of compound 32-b

[0233] I-5 (100.0 mg, 0.14 mmol), 32-a (77.5 mg, 0.27 mmol), potassium phosphate (116.2 mg, 0.55 mmol), XPhos Pd G3 (11.6 mg, 0.01 mmol) were dissolved in dioxane (6 mL) and water (2 mL), replaced with nitrogen three times, heated and stirred at 90 ° C for 2 h, and the reaction of the raw materials was completed by LC-MS monitoring. The mixture was cooled to room temperature, filtered and concentrated, and purified by reverse phase medium pressure preparation (ACN:H2O=70:30), and vacuum freeze-dried to obtain 25.0 mg of yellow oily compound 32-b. MS m / z (ESI): 807.30 [M+H] + .

[0234] Step 2: Synthesis of compound 32

[0235] 32-b (25.0 mg, 0.01 mmol) was added to a single-mouth bottle, DCM (5 mL) was added to dissolve, trifluoroacetic acid (2 mL) was added, and then the reaction was stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction by LC-MS monitoring, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by reverse phase medium pressure preparation (acetonitrile: water = 55:45, acid method), and vacuum freeze-dried to obtain 1.5 mg of white solid compound 32. MSm / z (ESI): 577.20 [M+H] + .

[0236] 1H NMR (400MHz, DMSO-d6) δ8.68(d,J=4.0Hz,1H),7.95(d,J=17.5Hz,1H),7.77(dd,J=8.2,6.4Hz,1H) ,7.64(dd,J=15.4,8.2Hz,1H),7.52(s,1H),7.33(s,1H),6.73(s,2H),5.64(d,J=13.9Hz,2H),4.09 (d, J = 8.4 Hz, 1H), 3.90 (s, 1H), 3.85 (d, J = 2.2 Hz, 3H), 3.80 (d, J = 10.2 Hz, 3H), 3.74 (d, J = 18.2 Hz, 1H), 3.57 (d, J = 28.8 Hz, 2H), 2.56 (s, 1H), 1.74 (s, 1H), 1.04 (s, 2H), 0.87 (d, J = 10.1 Hz, 2H). Preparation of compound 33

[0237]

[0238] Step 1: Synthesis of compound 33-a

[0239] Dissolve 7-a (2.0 g, 10.64 mmol) in a mixed solvent of acetonitrile (40 mL) and acetic acid (8 mL). Add 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (5.7 g, 16.0 mmol). Stir overnight at 80°C. Concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (PE:EA=10:1-2:1) to obtain 1.4 g of brown solid compound 33-a. MS m / z(ESI):205.96[M+H] + .

[0240] Step 2: Synthesis of compound 33-b

[0241] 33-a (1.4 g, 6.8 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Under nitrogen protection, sodium hydride (0.4 g, 10.2 mmol) was added in an ice bath. After stirring for half an hour in an ice bath, 2-(trimethylsilyl)ethoxymethyl chloride (2.4 mL, 13.6 mmol) was added. After stirring at room temperature for 1.5 hours, ice water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2*20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1-3:1) to obtain 1.6 g of light brown oily compound 33-b. MS m / z(ESI):336.04[M+H] + .

[0242] Step 3: Synthesis of compound 33-c

[0243] Referring to the synthesis of compound 1-c, 1-a was replaced by 33-b, and I-2 was replaced by I-3. MS m / z (ESI): 556.15 [M+H] + .

[0244] Step 4: Synthesis of compound 33-d

[0245] Referring to the synthesis of compound 1, 1-c was replaced by 33-c, and 1-d was replaced by 24-b. MS m / z (ESI): 660.23 [M+H] + .

[0246] Step 5: Synthesis of compound 33

[0247] 33-d (37.0 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. Stir at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. Tetrahydrofuran (1 mL) and ammonia water (1 mL) were added to the obtained residue, and stirred at room temperature for 30 minutes. Water (5 mL) was added, and extracted with ethyl acetate (2*5 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was first purified by silica gel column chromatography (PE:EA=10:1-1:3), and then purified by preparative purification, and lyophilized to obtain 7.7 mg of white solid compound 33. MS m / z(ESI):530.15[M+H] + .

[0248] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.60(s,1H),7.94(s,1H),7.77-7.71(m,2 H),7.69-7.60(m,2H),7.44-7.37(m,1H),5.62(s,2H),3.87(s,6H),3.79(s,3H).

[0249] Preparation of compound 35

[0250]

[0251] Step 1: Synthesis of compound 35-b

[0252] At room temperature, I-3-2 (21.9 g, 81.08 mmol) and sodium acetate (6.6 g, 81.08 mmol) were added to water (100 mL), and the resulting mixture was stirred and heated at 100 ° C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (200 mL) solution containing 35-a (10.0 g, 54.05 mmol), and then ammonia water (100 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was added to water (100 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:1) gave 11.8 g of 35-b. MS m / z(ESI):290.97[M+H] + .

[0253] Step 2: Synthesis of compound 35-c

[0254] Compound 35-b (11.8 g, 40.54 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (11.2 g, 81.07 mmol) and iodomethane (8.6 g, 60.8 mmol) were added, and the mixture was reacted at room temperature for 4 h. The reaction solution was added to ice water (500 mL), and extracted with ethyl acetate (3*100 mL). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=20:1-5:1) gave 11.0 g of 35-c. MS m / z(ESI):304.98[M+H] + .

[0255] Step 3: Synthesis of compound 35-d

[0256] Compound 35-c (2.4 g, 7.87 mmol), ethynyltrimethylsilane (2.3 g, 23.6 mmol), cuprous iodide (0.6 g, 3.15 mmol), bistriphenylphosphine palladium dichloride (1.1 g, 1.57 mmol) were dissolved in dioxane (20 mL), replaced with nitrogen three times, stirred at 80 ° C for 4 hours, the reaction solution was added to water (100 mL), and extracted with ethyl acetate (3*50 mL), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE: EA = 20: 1-3: 1) gave 2.2 g of 35-d. MS m / z (ESI): 323.11 [M+H] + .

[0257] Step 4: Synthesis of compound 35-e

[0258] Compound 35-d (2.2 g, 6.83 mmol) was dissolved in methanol (100 mL), potassium carbonate (1.9 g, 13.66 mmol) was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA=20:1-3:1) to obtain 1.47 g of 35-e. MS m / z (ESI): 251.07 [M+H] + .

[0259] Step 5: Synthesis of compound 35-f

[0260] Compound 35-e (200.0 mg, 0.8 mmol), compound 3-a (287.0 mg, 0.16 mmol), cuprous iodide (61.0 mg, 0.32 mmol), bistriphenylphosphine palladium dichloride (112.0 mg, 0.16 mmol) and triethylamine (1.1 mL, 8.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), replaced with nitrogen, stirred at 80 ° C for 16 hours, the reaction solution was added to water (30 mL), and extracted with ethyl acetate (3*20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:3) gave 230.0 mg 35-f. MS m / z(ESI):393.07[M+H] + .

[0261] Step 6: Synthesis of compound 35-g

[0262] Compound 35-f (220.0 mg, 0.56 mmol), compound 1-d (163.0 mg, 0.84 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (107.0 mg, 0.22 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (88.0 mg, 0.11 mmol), and potassium phosphate (357.0 mg, 1.68 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (1 mL), replaced with nitrogen, and stirred at 80°C for 3 hours. The reaction solution was added to water (10 mL), extracted with ethyl acetate (3*10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:4) gave 230.0 mg of 35-g. MS m / z (ESI): 507.17 [M+H] + .

[0263] Step 7: Synthesis of compound 35

[0264] Compound 35-g (230.0 mg, 0.45 mmol) was dissolved in methanol (10 mL), 10% palladium carbon (100 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 4 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, first purified by silica gel column chromatography (PE: EA = 20: 1-0: 1), and then purified by reverse phase medium pressure preparation (acetonitrile: water = 20: 1-1: 1, pure water) and freeze-dried to obtain 57.1 mg of compound 35. MS m / z (ESI): 511.2 [M+H] + .

[0265] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.61(s,1H),7.92(d,J=1.2Hz,1H),7.64-7.57(m,2H),7.37-7.30(m,2H),3.99(s,3H) ,3.86(s,3H),3.77(s,3H),3.22-3.14(m,2H),3.14-3.06(m,2H),1.59-1.50(m,1H),1.07-0.99(m,2H),0.90-0.82(m,2H).

[0266] Preparation of compound 36

[0267]

[0268] Step 1: Synthesis of compound 36-a

[0269] Compound I-5-1 (2.0 g, 6.3 mmol) was dissolved in tetrahydrofuran (20 mL), and tributyl vinyl tin (2.7 mL, 9.4 mmol) and bis(triphenylphosphine) palladium dichloride (0.2 g, 0.3 mmol) were added. Under nitrogen protection, the mixture was heated to reflux for 4 hours. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate (2*20 mL), and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 831.0 mg of compound 36-a was obtained by purification by silica gel column chromatography (PE:EA=20:1–8:1). MSm / z(ESI):310.2[M+H] + .

[0270] Step 2: Synthesis of compound 36-b

[0271] Compound 36-a (830.0 mg, 2.7 mmol), 1-d (1.0 g, 5.4 mmol), potassium phosphate (1.7 g, 8.1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.5 g, 1.1 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.4 g, 0.5 mmol), dioxane (10 mL), and water (2 mL) were added to a reaction flask. The mixture was stirred at 95° C. overnight under nitrogen protection. The mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=20:1–2:1) to obtain 651.0 mg of compound 36-b. MS m / z (ESI): 424.2 [M+H] + .

[0272] Step 3: Synthesis of compound 36-c

[0273] Compound 36-b (550.0 mg, 1.3 mmol), I-6 (629.3 mg, 2.0 mmol), sodium acetate (319.4 mg, 3.9 mmol), palladium acetate (58.3 mg, 0.26 mmol), tri(o-methylphenyl)phosphine (158.1 mg, 0.52 mmol), dimethylacetamide (10 mL) were added to the reaction bottle, nitrogen was protected, and the mixture was stirred at 150°C for 8 hours, and then stirred at 120°C overnight. Dilute with water, extract with ethyl acetate (2*10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1–1:1) to obtain 211.0 mg of compound 36-c. MS m / z(ESI):666.0[M+H] + .

[0274] Step 4: Synthesis of compound 36-d

[0275] Compound 36-c (211.0 mg, 0.32 mmol) was dissolved in methanol (8 mL), palladium carbon (80.0 mg) was added, and hydrogen was replaced. Stirred at room temperature for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 190.0 mg of compound 36-d. MS m / z (ESI): 667.7 [M+H] + .

[0276] Step 5: Synthesis of compound 36

[0277] Compound 36-d (58.0 mg, 0.1 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (3 mL) was added. Stir at room temperature for 3 hours and concentrate under reduced pressure. The residue after concentration was dissolved in tetrahydrofuran (2 mL), and ammonia water (4 mL) was added. Stir at room temperature for 1 hour. Extract with ethyl acetate (2*5 mL), wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by preparation and lyophilized to obtain 9.8 mg of compound 36. MS m / z (ESI): 538.0 [M+H] + .

[0278] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.66(s,1H),7.96(s,1H),7.54(d,J= 3.5Hz,1H),7.42(t,J=7.8Hz,1H),7.30(d,J=11.5Hz,1H),7.20(d,J=7.9Hz ,1H),6.72(d,J=3.5Hz,1H),3.83(s,3H),3.54(s,3H),3.44-3.38(m,2H),3 .26-3.20(m,2H),1.64-1.55(m,1H),1.06-1.00(m,2H),0.88-0.81(m,2H).

[0279] Preparation of compound 37

[0280]

[0281] Step 1: Synthesis of compound 37-a

[0282] Compound 36-d (130.0 mg, 0.2 mmol) was dissolved in dimethyl sulfoxide (5 mL), and N-iodosuccinimide (65.7 mg, 0.3 mmol) was added. The mixture was protected by nitrogen and reacted at 80°C for half an hour. The mixture was diluted with water, extracted with ethyl acetate (2*10 mL), washed with saturated sodium thiosulfate, then washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=10:1–1:1) to obtain 48.0 mg of compound 37-a. MS m / z(ESI):793.8[M+H] + .

[0283] Step 2: Synthesis of compound 37-b

[0284] Compound 37-a (48.0 mg, 0.06 mmol), cuprous cyanide (54.2 mg, 0.60 mmol), 1,1'-bis(diphenylphosphino)ferrocene (13.4 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (22.2 mg, 0.02 mmol), dioxane (5 mL) were added to the reaction flask. Stirred at 100 °C for 40 minutes under nitrogen protection. Filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1–1:1) to obtain 29.0 mg of compound 37-b. MS m / z(ESI):693.0[M+H] + .

[0285] Step 3: Synthesis of compound 37

[0286] Compound 37-b (29.0 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (3 mL) was added. Stir at room temperature for 3 hours and concentrated under reduced pressure. The residue after concentration was dissolved in tetrahydrofuran (2 mL), and ammonia water (4 mL) was added. Stir at room temperature for 1 hour. Extracted with ethyl acetate (2*5 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative purification and freeze-dried to obtain 8.8 mg of compound 37. MS m / z (ESI): 563.1 [M+H] + .

[0287] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.48(s,1H),7.96(s,1H),7.44(t,J=7.8Hz,1H),7.29(d,J=11.3Hz,1H),7.19(d,J=7.9Hz ,1H),3.83(s,3H),3.55(s,3H),3.54-3.48(m,2H),3.26-3.20(m,2H),1.66-1.55(m,1H),1.08-1.00(m,2H),0.88-0.80(m,2H).

[0288] Comparative compound KSQ-4279, the structural formula is The preparation method refers to CN113164485A.

[0289] Determination of IC by FI method 50 The inhibitory activity of compounds on USP1 was evaluated by

[0290] The test method 1 for compound 2-3 is as follows:

[0291] USP1 (R&D, Cat#E-568) enzyme solution (USP1 enzyme concentration is 0.05 nM) and Recombinant Human Ubiquitin Rhodamine 110 Protein (R&D, Cat#U-555) substrate solution (Recombinant Human Ubiquitin Rhodamine 110 Protein concentration is 200 nM) were prepared using reaction buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Tween-20, 0.01% BSA, 1 mM DTT). The compounds were diluted 3x in a gradient manner using DMSO (Sigma, D5879) (the final reaction system compound starting concentration was 10.0 μM, 3X dilution, a total of 10 concentration points). In a 384-well test plate (Coring), 0.05 μL of each compound diluted with 100% DMSO was added to each well of the compound group by acoustic liquid delivery technology (Echo650; nanoliter range), and 0.05 μL DMSO was added to each well of the blank group and protein control group; then 5 μL USP1 enzyme solution was added to each well of the compound group and protein control group, and 5 μL reaction buffer was added to each well of the blank group, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 15 minutes; finally, 5 μL Recombinant Human Ubiquitin Rhodamine 110 Protein substrate solution was added to each well of each group (the starting concentration of the compound gradient concentration in the compound group reaction system was 10.0 μM at this time), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Finally, the FI signal (ex480 / em520) was read using BMG (PHERAstar FSX). IC was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0292] The inhibition percentage (%) of each concentration of the compound was calculated based on the signals of the minimum fluorescence signal group (blank group) and the maximum fluorescence signal group (protein control group) contained in each test plate. The minimum fluorescence signal group had no enzyme and compound added, and the others were consistent with the compound group, with the minimum fluorescence signal, set to 100% inhibition, and the maximum fluorescence signal group had no compound added, and the others were consistent with the compound group, with the maximum fluorescence signal, set to 0% inhibition.

[0293] The inhibition rate of each compound concentration was calculated as follows: inhibition rate % = {1-[(maximum fluorescence signal group-compound group fluorescence signal) / (maximum fluorescence signal group-minimum fluorescence signal group)]}*100%. Finally, the four-parameter logistic dose-response equation was used to determine the compound concentration required for 50% inhibition, i.e., IC50 The results are shown in Table 1.

[0294] The remaining compounds were tested in method 2 as follows:

[0295] USP1 (R&D, U-555-050) enzyme solution (USP1 enzyme concentration is 0.03 nM) and Recombinant Human Ubiquitin Rhodamine 110 Protein (R&D, E-568-050) substrate solution (Recombinant Human Ubiquitin Rhodamine 110 Protein concentration is 450 nM) were prepared using reaction buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Tween-20, 0.01% BSA, 1 mM DTT). The 10 mM compound stock solution was diluted 11.11× with DMSO (Sigma, D5879), then 4× gradient dilution was performed, and then the compound was diluted 100× with reaction buffer (the final reaction system compound starting concentration was 3 μM, 4× dose dilution, a total of 8 concentration points). In a 384-well test plate (Coring, 3824), 5 μL of reaction buffer was added to each well of the blank group and the protein control group, and 5 μL of diluted compounds of each concentration were added to each well of the compound group. Then 5 μL of reaction buffer was added to each well of the blank group, and 5 μL of USP1 enzyme solution was added to each well of the protein control group and the compound group, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. Then 5 μL of Recombinant Human Ubiquitin Rhodamine 110 Protein substrate solution was added to each well of each group (at this time, the starting concentration of the compound gradient concentration in the compound group reaction system was 3 μM), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 30 minutes. Finally, a high-throughput drug screening multifunctional microplate reader (TECAN Spark) was used to read the luminescent signal of the reaction system in the FlourescenIntensity mode to read the FI signal (ex485 / em535). IC was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0296] The inhibition percentage (%) of each concentration of the compound is calculated based on the signals of the minimum fluorescence signal group (blank group) and the maximum fluorescence signal group (protein control group) contained in each test plate. The minimum fluorescence signal group has no added enzymes and compounds, and the others are consistent with the compound group. The fluorescence signal is the minimum and is set to 100% inhibition. The maximum fluorescence signal group has no added compounds, and the others are consistent with the compound group. The fluorescence signal is the maximum and is set to 0% inhibition. The inhibition rate of each compound concentration is calculated as follows: Inhibition rate % = {1-[(maximum luminescence signal group-luminescence signal of compound group) / (maximum luminescence signal group-minimum luminescence signal group)]}*100%. Finally, the four-parameter logistic dose-response equation is used to determine the compound concentration required for 50% inhibition, that is, IC 50 The results are shown in Table 1.

[0297] Table 1 USP1 inhibitory activity of compounds of the present invention

[0298] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> <![CDATA[KSQ-4279 1 ]]> 15.7 8 28.0 20 15.9 28 9.3 <![CDATA[KSQ-4279 2 ]]> 15.2 10 11.6 21 37.6 29 35.7 2 9.3 11 7.2 22 20.4 30 15.1 3 13.0 13 13.7 23 14.9 31 29.5 4 17.0 17 15.6 24 22.3 32 22.2 5 34.0 18 20.1 25 15.4 35 32.9 7 16.6 19 29.8 26 27.0 36 20.1

[0299] Note: KSQ-4279 1 Measured by method 1, KSQ-4279 2 Measured using method 2.

[0300] As can be seen from Table 1, the compounds of the present invention have excellent inhibitory activity against USP1 and can be used as drugs for preventing and / or improving and / or treating diseases related to this activity.

[0301] Cell assay evaluation

[0302] BRCA1 was cultured in complete medium DMEM (Gibco, 11963092) / 10% FBS (Gibco, 10099141C) / 1% ITS (Gibco, 41400045) / 1% GSH (Sigma, G6013-5G). - / - MDA-MB-436 cell line (Nanjing Kebai Biotechnology Co., Ltd.) was cultured with complete medium DMEM (Gibco, 11963092) / 20% FBS (Gibco, 10099141C) to culture wild-type CAL-51 cell line (Nanjing Kebai Biotechnology Co., Ltd.) to evaluate the effects of compounds on BRCA1 - / - Selective inhibition of cell proliferation of MDA-MB-436 and CAL-51 cell lines. Day 0, on a 96-well cell culture plate (Corning, 3599), BRCA1 - / -MDA-MB-436 cells were added to each well with 800 cells / 100 μL cell suspension, and wild-type CAL-51 cells were added to each well with 50 cells / 100 μL cell suspension, and cultured in a 37°C, 5% CO2 incubator. Day 1, 10 mM compound stock solution was diluted 2.5x with DMSO (Sigma, D5879), and then the compound was diluted 3x in a gradient, for a total of 10 concentration points. The starting concentration of wild-type CAL-51 cells was the first concentration point, and BRCA1 - / - The starting concentration of MDA-MB-436 cells was the third concentration point, and the compound was diluted 200x with the corresponding culture medium using a multichannel pipette (Rainin: Pipet-Lite XLS+) (the final starting concentration of wild-type CAL-51 cells in the culture medium was 20 μM, BRCA1 - / - The final starting concentration of MDA-MB-436 cells was 2.2 μM, all diluted 3x, and a total of 8 concentration points). Compounds of various concentrations were added to the cells as the compound group; the control group did not contain compounds, and the rest was the same as the compound group, with a final DMSO concentration of 0.5%. The compound group and the control group were cultured in a 37°C, 5% CO2 incubator for 10 days. The blank group contained 100 μL of the corresponding culture medium. On Day 11, 20 μL of MTS (CellTiter A Queous One Solution Cell Proliferation Assay (Promega, G3581), incubated in a 37°C, 5% CO2 incubator for 2 h, and read by Tecan Spark (OD = 490 nM). Then, data analysis software GraphPad Prism 8 was used, using the equation "log (inhibitor) vs. normalized response--variable slope" (formula Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))) to analyze the data and obtain the IC value of the compound 50 Where Y is the inhibition rate, X is the logarithmic value of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), and Hill Slope refers to IC 50 The slope of the curve, IC 50 is the concentration of compound that results in half inhibition.

[0303] Table 2 Inhibitory activity of the compounds of the present invention on MDA-MB-436 cells

[0304] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> KSQ-4279 31.6 13 10.4 20 41.0 28 7.6 5 18.7 14 15.9 21 27.2 29 21.5 7 6.2 15 20.8 22 20.7 30 23.8 10 14.6 17 9.6 23 8.1 34 8.5 11 6.7 18 4.9 24 38.3 12 42.2 19 28.3 25 7.8

[0305] As can be seen from Table 2 above, the compounds of the present invention have an effect on BRCA1 - / - It has excellent inhibitory effect on MDA-MB-436 cell proliferation.

[0306] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof: in, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5) or NR6; L is selected from C=O, C(R7)(R8), O, S or Se; R6 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R7 and R8 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl or C 2-6 The 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Each alkynyl group is independently unsubstituted or substituted with one or more R a replace; R1 is selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace; or R1 and R2 are combined with the atoms to which they are connected to form a phenyl group, a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group each independently contains 1 to 3 heteroatoms selected from N, O and S, and the phenyl group, the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group each independently is unsubstituted or substituted by one or more R a replace; R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form a C 3-6 Cycloalkyl; or R3 and R4, together with the atoms to which they are attached, form a 5-6 membered heterocycloalkenyl or C 5-6 The 5-6 membered heterocycloalkenyl contains 1-3 heteroatoms selected from Se, O and S, and the 5-6 membered heterocycloalkenyl, C 5-6 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R a replace; Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R b replace; B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R c replace; Each R b and R c are independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; or R 11 and R 12 The P to which they are connected together forms a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace; or R 17 and R 18 The atoms to which they are attached together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace; C is selected from -C(O)NR i R j , C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 6-10 The aryl group, the 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group are each independently unsubstituted or substituted with one or more R d replace; Each R d Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; Each R a are independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NR i R j , C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R e replace; Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R f replace; Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; Each R i , R j , R k are independently selected from the same or different hydrogen or C 1-6 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: X1 is selected from CR2, X2 is selected from N; R2 is selected from H, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl, the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Each alkenyl group is independently unsubstituted or substituted with one or more R a replace; Preferably, R2 is selected from H, halogen, amino, C 1-4 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, the amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Each alkenyl group is independently unsubstituted or substituted with one or more R a replace; Preferably, R2 is selected from H, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyl, propenyl or butenyl, and the amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyl, propenyl, butenyl are each independently unsubstituted or substituted by one or more R a replace; Preferably, R2 is selected from H, F, Cl, amino, methyl, methoxy or vinyl, wherein the amino, methyl, methoxy and vinyl are each independently unsubstituted or substituted by one or more R a replace; Preferably, R2 is selected from H, F, Cl, amino, methyl, methoxy or vinyl, wherein the amino and methyl groups are each independently unsubstituted or substituted by one or more R a replace; Each R a are independently selected from the same or different cyano or C 1-6 alkyl; Preferably, each R a Each independently selected from the same or different cyano group, C 1-4 Alkyl or C 5-6 alkyl; Preferably, each R a each independently selected from the same or different cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a are each independently selected from the same or different cyano or methyl groups; Preferably, R2 is selected from H, F, Cl, methoxy, amino, methyl, or vinyl; Preferably, X1 is CR2, X2 is N, and R2 is selected from H, F, Cl, methoxy, amino, methyl, or vinyl; Most preferably, X1 is CR2, X2 is N, and R2 is selected from methyl; Most preferably, X1 is CR2, X2 is N, and R2 is selected from methoxy; or, R1 is selected from H, halogen, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the amino, C 1-6 The alkoxy groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, R1 is selected from H, halogen, cyano, amino, C 1-4 Alkyl or C 1-4 Alkoxy, the amino, C 1-4 The alkoxy groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, R1 is selected from H, F, Cl, Br, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, wherein the amino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy are each independently unsubstituted or substituted by one or more R a replace; Preferably, R1 is selected from H, Cl, cyano, amino, methyl or methoxy, wherein the amino and methoxy are each independently unsubstituted or substituted by one or more R a replace; Preferably, R1 is selected from H, Cl, cyano, amino, methyl or methoxy, wherein the amino is unsubstituted or substituted by one or more R a replace; Each R a Each independently selected from the same or different C 1-6 alkyl; Preferably, each R a Each independently selected from the same or different C 1-4 Alkyl or C 5-6 alkyl; Preferably, each R a Each is independently selected from the same or different methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a are each independently selected from the same or different methyl groups; Preferably, R1 is selected from H, Cl, methyl, cyano, methoxy, amino, Most preferably, R1 is selected from H.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: X1 is selected from CR2, X2 is selected from N, then for R1 and R2 are combined with the atoms to which they are connected to form a phenyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, a 5-membered heterocyclic group or a 5-membered heteroaryl group; the 5-membered heterocyclic group and the 5-membered heteroaryl group each independently contain 1 to 3 heteroatoms selected from N, O and S; the phenyl group, the pyridyl group, the pyrimidyl group, the pyrazinyl group, the pyridazinyl group, the 5-membered heterocyclic group and the 5-membered heteroaryl group each independently are unsubstituted or substituted by one or more R a replace; Preferably, R1 and R2 are combined with the atoms to which they are connected to form phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl or 5-membered heterocycloalkenyl; the 5-membered heterocycloalkenyl contains 1-2 N heteroatoms; the phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, 5-membered heterocycloalkenyl are each independently unsubstituted or substituted by one or more R a replace; Preferably, R1 and R2 are combined with the atoms to which they are connected to form phenyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl or 5-membered heterocycloalkenyl; the 5-membered heterocycloalkenyl contains 1-2 N heteroatoms; the phenyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, 5-membered heterocycloalkenyl are each independently unsubstituted or substituted with one or more R a replace; Preferably, Selected from Preferably, each R a are independently selected from the same or different halogen, cyano, =O, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NR i R j , C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, the amino, C 1-6 The alkyl group and the 4-7 membered heterocycloalkyl group are each independently unsubstituted or substituted with one or more R e Replace; each R e are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy; R i , R j are independently selected from the same or different hydrogen or C 1-6 alkyl; Preferably, each R a are independently selected from the same or different halogen, cyano, =O, amino, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR i R j , C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, and the amino, C 1-4 The alkyl group and the 4-7 membered heteroalkyl ring group are each independently unsubstituted or substituted with one or more R e Replace; each R e are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy; R i , R j are independently selected from the same or different hydrogen or C 1-4 alkyl; Preferably, each R a are independently selected from the same or different halogen, cyano, =O, amino, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, -C(O)NR i R j , C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the amino, C 1-2 Alkyl, C 3-4 The alkyl group and the 4-7 membered heterocycloalkyl group are each independently unsubstituted or substituted with one or more R e Replace; each R e are independently selected from the same or different halogen, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Fluorinated alkyl, C 3-4 Fluorinated alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy; R i , R j are independently selected from the same or different hydrogen or C 1-2 alkyl; Preferably, each R a each independently selected from the same or different F, Cl, Br, cyano, =O, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -C(O)NR i R j , vinyl, propenyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the amino, methyl, ethyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R e Replace; each R e Each is independently selected from the same or different F, Cl, Br, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy; R i , R j Each is independently selected from the same or different hydrogen, methyl, ethyl; Preferably, each R a each independently selected from the same or different F, Cl, Br, cyano, =O, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -C(O)NR i R j , vinyl, propenyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the amino is unsubstituted or substituted by one or more identical or different methyl, ethyl, fluoromethyl or fluoroethyl, the methyl or ethyl are each independently unsubstituted or substituted by one or more identical or different F, Cl, Br, methoxy or ethoxy, the 4-7 membered heterocycloalkyl is unsubstituted or substituted by one or more identical or different methyl or ethyl; R i , R j Each is independently selected from the same or different hydrogen, methyl, ethyl; Preferably, each R a Each is independently selected from the same or different =O, methyl, isopropyl, cyclopropyl, vinyl, ethynyl, F, Cl, -CF3, methoxy, cyano, Amino, Most preferably, X1 is selected from CR2, X2 is selected from N, then for Selected from Preferably, X1 is CR2, X2 is N; R1 and R2 are combined with the atoms to which they are connected to form a phenyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O and S, and the phenyl group, the pyridyl group, the pyrimidyl group, the pyrazinyl group, the pyridazinyl group and the 5-membered heteroaryl group are each independently unsubstituted or substituted by one or more R a replace; Preferably, X1 is CR2, X2 is N; R1 and R2 are combined with the atoms to which they are connected to form phenyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, and the phenyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, pyrrolyl are each independently unsubstituted or substituted with one or more R a replace; Each R a Each independently selected from the same or different C 1-6 alkyl; Preferably, each R a Each independently selected from the same or different C 1-4 Alkyl or C 5-6 alkyl; Preferably, each R a Each is independently selected from the same or different methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a are each independently selected from the same or different methyl groups; Most preferably, Selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: Selected from or Selected from or Selected from 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: L is selected from C=O, C(R7)(R8), O, S or Se; R7 and R8 are each independently selected from H, deuterium, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; Preferably, L is selected from C=O, C(R7)(R8), O, S or Se; R7 and R8 are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; Preferably, L is selected from methylene, C=O, O, S or Se; Preferably, L is selected from O; or, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium or C 1-6 alkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, C 1-4 Alkyl or C 5-6 alkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium or methyl; M is selected from C(R4)(R5); R4 and R5 are each independently selected from H or C 1-6 alkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, C 1-4 Alkyl or C 5-6 alkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H or methyl; Most preferably, M is selected from methylene.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl or phenyl and 6-membered heteroaryl, the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl, phenyl and 6-membered heteroaryl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 N heteroatoms, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, benzopyrazolyl or benzimidazolyl, wherein the phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, benzopyrazolyl, benzimidazolyl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl or benzopyrazolyl, wherein the phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl and benzopyrazolyl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from Each R b are independently selected from the same or different halogen, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 alkyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each independently selected from H or C 1-4 alkyl; Preferably, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-3 heteroatoms selected from N, O and S. 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each independently selected from H or C 1-4 alkyl; Preferably, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O and S. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each independently selected from H or C 1-4 alkyl; Preferably, each R b each independently selected from the same or different F, Cl, Br, amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl contains 1 N heteroatom, and the amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Replacement; R i , R j , R k are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, each R b each independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k 、-C(O)NR i R j , The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k are each independently selected from hydrogen, methyl or ethyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 are each independently selected from hydrogen, methyl or ethyl; Preferably, each R b Each is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a replace; Each R a Each independently selected from the same or different halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy; Preferably, each R a Each independently selected from the same or different halogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy; Preferably, each R a each independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; Preferably, each R a Each independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy; Preferably, each R a Each independently selected from the same or different F, hydroxy, methyl or methoxy; Preferably, each R b Each is independently selected from the same or different F, Cl, amino, methyl-substituted amino, -SCH3, methyl, fluoromethyl, methoxy, fluoromethoxy, ethoxy, fluoroethoxy, hydroxy-substituted isopropyl, hydroxy-substituted cyclopropyl, methoxy-substituted ethoxy, isopropyl, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, Preferably, each R b Each is independently selected from the same or different methyl, methoxy, cyclopropyl, isopropyl, ethoxy, isopropoxy, -SCH3, -SeCH3, Amino, F, Cl, -OCHF2, -OCF3, -CF3, Most preferably, Ring A is selected from or, B is selected from C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O and S. 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen or C 1-6 Alkoxy substitution; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-8 The 5-membered heteroaryl, 6-membered heteroaryl, and 4-7-membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O, and S. 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-8 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen or C 1-4 Alkoxy substitution; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-6 The 6-membered heteroaryl and 4-7-membered heterocycloalkyl groups each independently contain 1-2 heteroatoms selected from N. 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen or C 1-4 Alkoxy substitution; Preferably, B is selected from ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl or piperazinyl, wherein the propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl and piperazinyl are each independently unsubstituted or substituted by one or more identical or different halogens, C 1-2 Alkoxy or C 3-4 Alkoxy substitution; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidyl, cyclohexyl or piperidyl, wherein the phenyl, pyridyl, pyrimidyl, cyclohexyl or piperidyl are each independently unsubstituted or substituted with one or more identical or different F, Cl, Br, methoxy or ethoxy groups; Preferably, B is selected from phenyl, pyridyl, pyrimidyl, cyclohexyl, piperidyl, fluoropiperidyl or ethynyl, wherein the phenyl is unsubstituted or substituted by one or more identical or different F or methoxy groups; Preferably, B is selected from or ethynyl; B is selected from C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O and S. 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-8 The 5-membered heteroaryl, 6-membered heteroaryl, and 4-7-membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O, and S. 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-8 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-6 The 6-membered heteroaryl and 4-7-membered heterocycloalkyl groups each independently contain 1-2 heteroatoms selected from N. 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl or piperazinyl, and the ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl, piperazinyl are each independently unsubstituted or substituted by one or more identical or different halogens; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidyl, cyclohexyl or piperidyl, wherein the ethynyl, phenyl, pyridyl, pyrimidyl, cyclohexyl or piperidyl are each independently unsubstituted or substituted with one or more identical or different F, Cl or Br; Preferably, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl or ethynyl; Preferably, B is selected from or ethynyl; or, C is selected from -C(O)NR i R j , C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R d Replacement; R i , R j are each independently selected from hydrogen, C 1-4 Alkyl or C 5-6 alkyl; Preferably, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R d Replacement; R i , R j Each independently selected from H or C 1-4 alkyl; Preferably, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, the 5-membered heteroaryl contains 1-2 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R d Replacement; R i , R j are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, said phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, said phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl are each independently unsubstituted or substituted by one or more R d Replacement; R i , R j are each independently selected from hydrogen, methyl or ethyl; Preferably, C is selected from -C(O)NHCH3, -C(O)N(CH3)2, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, and the pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl are each independently unsubstituted or substituted with one or more R d replace; Preferably, C is selected from Each R d are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, the C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1 N heteroatom, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d R is each independently selected from the same or different F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or azetidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl are each independently unsubstituted or replaced by one or more R a replace; Preferably, each R d Each is independently selected from the same or different F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl is each independently unsubstituted or substituted by one or more R a replace; Preferably, each R d Each is independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl is each independently unsubstituted or substituted by one or more R a replace; Each R a are independently selected from the same or different halogen, =O or C 1-6 alkyl; Preferably, each R a are independently selected from the same or different halogen, =O or C 1-4 alkyl; Preferably, each R a Each is independently selected from the same or different F, Cl, Br, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a Each is independently selected from the same or different F, =O or methyl; Preferably, each R d Each is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl, Preferably, each R d Each independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3; Most preferably, C is selected from 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: Selected from the following structures:

8. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, wherein the compound is selected from the following structures:

9. A pharmaceutical composition, characterized in that: Comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

10. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating tumors or cancer; Preferably, the tumor or cancer is associated with USP1 biological activity; Preferably, the tumor or cancer refers to a tumor or cancer associated with USP1 biological activity and having HR deficiency; Preferably, the tumor or cancer is a cancer or tumor with HR deficiency.

Images