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) have more than 50 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 many 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] Preparation method:

[0007]

[0008] Step 1: The compound represented by Formula IA-1 and the compound represented by Formula IA-2 are subjected to coupling reaction to obtain the compound represented by Formula IA-3;

[0009] 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;

[0010] Wherein, X1, X2, X3, X4, L, ring A, B, and C are as defined above.

[0011] Beneficial effects of the present invention:

[0012] 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

[0013] Preparation of intermediate int-a

[0014]

[0015] Step 1: Synthesis of compound int-ac

[0016] At room temperature, int-ab (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 int-aa (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 a white solid compound int-ac. MS m / z(ESI):271.06[M+H] + .

[0017] Step 2: Synthesis of compound int-ad

[0018] Dissolve the compound int-ac (3.0 g, 11.0 mmol) in N,N-dimethylformamide (30 mL), and add sodium hydride (60%, 0.67 g, 17.0 mmol) in batches at 0°C. Stir the reaction solution at 0°C for 0.5 h, then add iodomethane (3.2 g, 22.0 mmol), and slowly return to room temperature to react for 2 h. Add the reaction solution into ice water (30 mL), and extract with ethyl acetate (3*20 mL). After the organic phases are combined, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 3.0 g of white solid compound int-ad. MS m / z (ESI): 285.08 [M+H] + .

[0019] Step 3: Synthesis of compound int-ae

[0020] Compound int-ad (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 filtrates were combined and concentrated under reduced pressure to remove the solvent to obtain 3.0 g of oily compound int-ae. MS m / z (ESI): 257.08 [M+H] + .

[0021] Step 4: Synthesis of compound int-af

[0022] Dissolve int-ae (2g, 7.78mmol) and triphenylphosphine (3.1g, 11.67mmol) in acetonitrile (40mL), add carbon tetrabromide (3.9g, 11.67mmol) at 0℃, and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (EA:PE=0-30%) to obtain 1.5g of white solid product compound int-af. MS m / z(ESI):319.00[M+H] + .

[0023] Step 5: Synthesis of compound int-a

[0024] Under nitrogen protection, compound int-af (1.0 g, 3.1 mmol), biboronic acid pinacol ester int-ag (1.2 g, 4.7 mmol), potassium acetate (913.0 mg, 9.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (117.0 mg, 0.16 mmol) were dissolved in dioxane (20 mL), stirred at 100°C for 4 hours, 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 = 0–25%) to obtain 0.7 g of white solid compound int-a. MS m / z (ESI): 367.17 [M+H] + .

[0025] Preparation of intermediate int-b

[0026]

[0027] The synthesis of intermediate int-b refers to intermediate int-a. MS m / z(ESI):395.1[M+H] + .

[0028] Preparation of intermediate int-c

[0029]

[0030] The synthesis of intermediate int-c refers to intermediate int-a. MS m / z(ESI):385.16[M+H] + .

[0031] Preparation of intermediate int-cg

[0032]

[0033] Step 1: Synthesis of compound int-cf

[0034] Under nitrogen protection, int-ce (8.0 g, 23.73 mmol) and trimethylsilyl cyanide (3.7 g, 33.22 mmol) were dissolved in acetonitrile (150 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (30.85 mL, 1 M) was added under ice bath, and stirred at room temperature for 2 hours. Water (100 mL) was added, and ethyl acetate (2*100 mL) was extracted, washed with saturated brine, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=20:1–3:1) to obtain 4.1 g of compound int-cf. MS m / z(ESI):284.1[M+H] + .

[0035] Step 2: Synthesis of compound int-cg

[0036] Dissolve int-cf (4.1 g, 14.48 mmol) in methanol (50 mL), add trimethylsilyl chloride (10.97 mL, 86.86 mmol) at room temperature, and stir at 65 ° C overnight. Concentrate the reaction solution under reduced pressure, dilute the residue with water, adjust pH to 7-8 with saturated sodium bicarbonate, extract with ethyl acetate (2*50 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 is purified by silica gel column chromatography (PE:EA=20:1-2:1) to obtain 3.8 g of compound int-cg. MS m / z(ESI):317.1[M+H] + .

[0037] Preparation of intermediate int-d

[0038]

[0039] The synthesis of intermediate int-d refers to intermediate int-a. MS m / z(ESI):413.30[M+H] + .

[0040] Preparation of intermediate int-e

[0041]

[0042] The synthesis of intermediate int-e refers to intermediate int-a. MS m / z(ESI):385.2[M+H] + .

[0043] Preparation of intermediate int-f

[0044]

[0045] Step 1-4: Synthesis of intermediate int-fe was based on intermediate int-af. MS m / z (ESI): 319.9 [M+H] + .

[0046] Step 5-6: Synthesis of intermediate int-f with reference to intermediate int-cg. MS m / z (ESI): 300.1 [M+H] + .

[0047] Preparation of intermediate int-g

[0048]

[0049] The synthesis of intermediate int-g refers to intermediate int-f. MS m / z(ESI):328.0[M+H] + .

[0050] Preparation of intermediate int-h

[0051]

[0052] Step 1: Synthesis of compound int-hc

[0053] Dissolve the hydrochloride of int-ha (9.0 g, 44.4 mmol) and int-hb (6.8 g, 44.4 mmol) in hexafluoroisopropanol (70 mL), add triethylamine (8.9 g, 87.9 mmol) dropwise at 0°C, and stir at room temperature for 2 h. Concentrate under reduced pressure, and separate the residue by silica gel column chromatography (PE:EA=10:1) to obtain 9.2 g of white solid int-hc. MS m / z(ESI):285.08[M+H] + .

[0054] Step 2-4: Synthesis of intermediate int-h was based on intermediate int-a. MS m / z (ESI): 367.43 [M+H] + .

[0055] Preparation of intermediate int-i

[0056]

[0057] Step 1: Synthesis of compound int-ic

[0058] Under nitrogen protection, int-ia (3.0 g, 35.19 mmol) and int-ib (5.0 g, 35.19 mmol) were dissolved in 100 mL of tetrahydrofuran and 100 mL of methanol, and sodium methoxide (14.08 mL, 5 mol / L) was added. The mixture was stirred at 60°C overnight. After the reaction was completed, it was cooled in an ice-water bath, and 2N dilute hydrochloric acid was added to the mixture to quench the reaction. It was extracted with ethyl acetate (3*50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, and separated and purified using a normal phase chromatography column (PE:EA=40:1) to obtain 4.0 g of colorless oily liquid int-ic. MS m / z(ESI):181.04[M+H] + .

[0059] Step 2: Synthesis of compound int-id

[0060] Dissolve the hydrochloride of int-ha (3.7 g, 22.21 mmol) and int-ic (4 g, 22.21 mmol) in hexafluoroisopropanol (70 mL), add sodium acetate (1.8 g, 22.21 mmol) dropwise at 0°C, and stir at room temperature for 2 h. Concentrate under reduced pressure, and separate the residue by silica gel column chromatography (PE:EA=10:1) to obtain 4.0 g of white solid int-id. MS m / z(ESI):311.08[M+H] + .

[0061] Step 3-5: Synthesis of intermediate int-i was based on intermediate int-a. MS m / z (ESI): 393.30 [M+H] + .

[0062] Preparation of intermediate int-j

[0063]

[0064] Step 1: Synthesis of compound int-jb

[0065] The compound int-ja (24.0 g, 104.8 mmol) was dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (29.0 g, 209.6 mmol) and iodomethane (9.8 mL, 157.21 mmol) were added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was added to water (1000 mL), extracted with ethyl acetate (3*300 mL), and the organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=1:0–1:5) gave 22.5 g of int-jb. MS m / z(ESI):242.96[M+H] + .

[0066] Step 2: Synthesis of compound int-jc

[0067] The synthesis of intermediate int-jc refers to intermediate int-ac, replacing int-aa with int-jb. MS m / z(ESI):348.97[M+H] + .

[0068] Step 3: Synthesis of compound int-jd

[0069] Compound int-jc (8.6 g, 24.63 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (6.8 g, 49.27 mmol) and benzyl bromide (6.3 g, 36.95 mmol) were added, and the mixture was reacted at room temperature for 4 h. The reaction solution was added to ice water (500 mL), extracted with ethyl acetate (3*200 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 8.3 g of int-jd. MS m / z(ESI):439.02[M+H] + .

[0070] Step 4: Synthesis of compound int-je

[0071] Under nitrogen protection, compound int-jd (3.3 g, 7.51 mmol) was dissolved in triethylamine (30 mL), but-3-yn-2-ol (2.87 g, 22.54 mmol, 55% in water), bistriphenylphosphine palladium dichloride (1.05 g, 1.5 mmol) and cuprous iodide (572 mg, 3.0 mmol) were added, and stirred at 80 ° C for 12 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (3*20 mL), and 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 = 1: 0–1: 1) gave 2.4 g int-je. MS m / z (ESI): 429.13 [M+H] + .

[0072] Step 5: Synthesis of compound int-jf

[0073] Dissolve the compound int-je (2.4 g, 5.6 mmol) in methanol (30 mL), add palladium carbon (500.0 mg) and palladium hydroxide (500.0 mg), replace with hydrogen, heat to 50°C for 12 hours, filter with diatomaceous earth, and concentrate the filtrate to obtain a crude product 2.4 g int-jf. MS m / z (ESI): 433.17 [M+H] + .

[0074] Step 6: Synthesis of compound int-jg

[0075] Dissolve the compound int-jf (2.4 g, 5.6 mmol) in tetrahydrofuran (30 mL), add palladium carbon (500.0 mg) and palladium hydroxide (500.0 mg), replace with hydrogen, heat to 50°C for 12 hours, filter with diatomaceous earth, and concentrate the filtrate to obtain a crude product of 1.3 g int-jg. MS m / z (ESI): 343.12 [M+H] + .

[0076] Step 7: Synthesis of compound int-jh

[0077] Under nitrogen protection, compound int-jg (1.2 g, 3.5 mmol) was dissolved in tetrahydrofuran (10 mL), triphenylphosphine (3.68 g, 14.02 mmol) was added, the temperature was lowered to 0 ° C, diethyl azodicarboxylate (12.44 g, 14.02 mmol) was added dropwise, and the temperature was naturally raised to room temperature for 12 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (3*10 mL), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=1:0–1:2) gave 1.08 g of int-jh. MS m / z(ESI):325.11[M+H] + .

[0078] Step 8-10: Synthesis of intermediate int-j was based on intermediate int-a. MS m / z (ESI): 407.2 [M+H] + .

[0079] Preparation of intermediate int-k

[0080]

[0081] Step 1: Synthesis of compound int-kb

[0082] Under nitrogen protection, compound int-jd (4.0 g, 9.11 mmol), compound int-ka (7.65 g, 45.55 mmol), tetrakistriphenylphosphine palladium (1.05 g, 0.91 mmol), sodium carbonate (1.93 g, 18.21 mmol) were dissolved in a mixed solution of dioxane (50 mL) and water (10 mL), stirred at 85 ° C for 6 hours, the reaction solution was added to water (100 mL), 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 = 1: 0–3: 1) gave 3.2 g of int-kb. MS m / z (ESI): 401.14 [M+H] +.

[0083] Step 2: Synthesis of compound int-kc

[0084] The compound int-kb (3.0 g, 7.49 mmol) was dissolved in tetrahydrofuran (50 mL), replaced with nitrogen, cooled to 0 ° C, and borane-tetrahydrofuran complex (22.5 mL, 22.47 mmol) was added dropwise. The temperature was naturally raised to room temperature for 3 hours, and then hydrogen peroxide (20 mL) was slowly added under an ice-water bath. The reaction was reacted at room temperature for 1 hour. 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 = 1: 0–1: 2) gave 1.45 g int-kc. MS m / z (ESI): 419.15 [M+H] + .

[0085] Step 3: Synthesis of compound int-kd

[0086] The compound int-kc (1.35 g, 3.23 mmol) was dissolved in methanol (20 mL), palladium carbon (100.0 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain a crude product of 0.9 g int-kd. MS m / z (ESI): 329.1 [M+H] + .

[0087] Step 4: Synthesis of compound int-ke

[0088] The synthesis of intermediate int-ke was based on intermediate int-jh. MS m / z(ESI):311.09[M+H] + .

[0089] Step 5-7: Synthesis of intermediate int-k was based on intermediate int-a. MS m / z (ESI): 393.19 [M+H] + .

[0090] Preparation of intermediate int-1

[0091]

[0092] The synthesis of intermediate int-1 refers to intermediate int-a. MS m / z(ESI):393.30[M+H] + .

[0093] Preparation of intermediate int-m

[0094]

[0095] The synthesis of intermediate int-m refers to intermediate int-a. MS m / z(ESI):370.43[M+H] + .

[0096] Example 1 Preparation of Compound 1

[0097]

[0098] Step 1: Synthesis of compound 1-b

[0099] 1-a (1.0 g, 5.29 mmol) was dissolved in 20 mL of tetrahydrofuran, PPTS (0.7 g, 2.65 mmol) and DHP (0.9 g, 10.58 mmol) were added, and the mixture was reacted at 60°C for 2 hours. After the reaction was completed, 100 mL of water was added to the mixture, and it was extracted with ethyl acetate (3*30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, which was separated and purified using a normal phase chromatography column (PE:EA=8:1) to obtain 1.2 g of white solid 1-b. MS m / z (ESI): 273.00 [M+H] + .

[0100] Step 2: Synthesis of compound 1-c

[0101] Under nitrogen protection, zinc powder (784.5 mg, 12 mmol) and iodine (76.1 mg, 0.3 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred at 30 ° C for 10 minutes. Trimethylsilyl chloride (32.6 mg, 0.3 mmol) was added, and the mixture was stirred at 45 ° C for 30 minutes. Int-af (319.0 mg, 1 mmol) was added, and the mixture was stirred at 45 ° C for 1 hour. 1-b (273.0 mg, 1 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.05 mmol) were added, and the mixture was stirred at 60 ° C overnight. After the reaction was completed, 200 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture. The mixture was separated and purified by a normal phase chromatography column (PE:EA=8:1) to obtain 200.0 mg of white solid 1-c. MS m / z(ESI):477.10[M+H] + .

[0102] Step 3: Synthesis of compound 1-e

[0103] Under nitrogen protection, 1-c (200.0 mg, 0.42 mmol) was dissolved in 5 mL of dioxane, 1 mL of water was added, 1-d (81.4 mg, 0.42 mmol), Pd(dppf)Cl2 (30.7 mg, 0.04 mmol) and potassium carbonate (116.0 mg, 0.84 mmol) were added, and the mixture was stirred at 100°C overnight. After the reaction was completed, 50 mL of water was added to the mixture, and it was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, which was separated and purified using a normal phase chromatography column (PE:EA=4:1) to obtain 160.0 mg of a white solid 1-e. MS m / z(ESI):591.26[M+H] + .

[0104] Step 4: Synthesis of compound 1

[0105] 1-e (20.0 mg, 0.03 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added to the mixture, and the pH was adjusted to weak alkalinity with sodium bicarbonate solution, and extracted with ethyl acetate (3*10 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, which was separated and purified using a reverse phase chromatography column (ACN:H2O=55%:45%) to obtain 3.0 mg of white solid compound 1. MS m / z (ESI): 507.18 [M+H] + .

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 14.17 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 4.59 (s, 2H), 3.87 (s, 3H), 3.77 (d, J = 8.2 Hz, 3H), 1.72-1.60 (m, 1H), 1.12-1.03 (m, 2H), 0.93-0.86 (m, 2H). Example 2 Preparation of Compound 2

[0107]

[0108] Step 1: Synthesis of compound 2-b

[0109] Under nitrogen protection, compound 2-a (2.0 g, 10.64 mmol) was dissolved in dry N, N-dimethylformamide (35 mL). Sodium hydride (0.9 g, 21.28 mmol) was added under ice bath, stirred under ice bath for half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (2.7 g, 15.96 mmol) was added, stirred at room temperature for 2 hours, the reaction solution was slowly poured into ice water, 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 normal phase medium pressure preparation (EA:PE=0–20%) to obtain 3.2 g of transparent oily compound 2-b. MS m / z(ESI):318.05[M+H] + .

[0110] Step 2: Synthesis of compound 2-c

[0111] Under nitrogen protection, compound 2-b (500.0 mg, 1.57 mmol), int-a (868.0 mg, 2.36 mmol), potassium phosphate (1000.5 mg, 4.71 mmol), bis(triphenylphosphine)palladium dichloride (55.1 mg, 0.08 mmol) were dissolved in toluene (9 mL) and water (3 mL) and stirred at 90 ° C overnight. Extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sulfuric acid, 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 = 0-60%) to obtain 245.0 mg of light yellow oily compound 2-c. MS m / z (ESI): 522.16 [M+H] + .

[0112] Step 3: Synthesis of compound 2-d

[0113] Under nitrogen protection, compound 2-c (245.0 mg, 0.47 mmol), 1-d (273.2 mg, 1.41 mmol), potassium phosphate (298.9 mg, 1.41 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (39.7 mg, 0.05 mmol) were dissolved in dioxane (6 mL) and water (2 mL) and stirred at 100 ° C for 2 hours. 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 purified by normal phase medium pressure preparation (EA:PE=5-60%) to obtain 177.0 mg of nitrogen brown oil compound 2-d. MS m / z (ESI): 636.27 [M+H] + .

[0114] Step 4: Synthesis of compound 2

[0115] Compound 2-d (70.0 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. Tetrahydrofuran (2 mL) and ammonia water (2 mL) were added to the obtained residue, stirred at room temperature for half an hour, 5 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 = 10-75%), and 25.4 mg of white solid compound 2 was obtained after freeze-drying. MS m / z (ESI): 506.18 [M+H] + .

[0116] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.66(s,1H),7.91-7.88(m,1H),7.63(d,J=8.2Hz,2H),7.57(dd,J=3.4,2.2Hz,1H),7.53(d,J=8. 2Hz,2H),6.76(dd,J=3.4,1.6Hz,1H),4.44(s,2H),3.83(s,3H),3.74(s,3H),1.70-1.58(m,1H),1.06-0.99(m,2H),0.86-0.79(m,2H).

[0117] Example 3 Preparation of Compound 3

[0118]

[0119] Step 1: Synthesis of compound 3-a

[0120] Compound 2-d (107.0 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (8 mL), N-bromosuccinimide (35.9 mg, 0.20 mmol) was added, stirred at room temperature for 1 hour, 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 = 5–65%) to obtain 102.0 mg of compound 3-a. MS m / z (ESI): 714.18 [M+H] + .

[0121] Step 2: Synthesis of compound 3-b

[0122] Under nitrogen protection, compound 3-a (102.0 mg, 0.14 mmol) was dissolved in dioxane (8 mL), and cuprous cyanide (127.9 mg, 1.43 mmol), 1,1'-bis(diphenylphosphino)ferrocene (31.6 mg, 0.06 mmol), tris(dibenzylideneacetone)palladium (52.3 mg, 0.06 mmol) were added, and stirred at 100°C overnight. Filter, concentrate the filtrate under reduced pressure to obtain a crude product, and the crude product was purified by normal phase medium pressure preparation (EA:PE=5-60%) to obtain 35.0 mg of compound 3-b. MS m / z(ESI):661.26[M+H] + .

[0123] Step 3: Synthesis of compound 3

[0124] Compound 3-b (35.0 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. Tetrahydrofuran (2 mL) and ammonia water (2 mL) were added to the obtained residue, stirred at room temperature for half an hour, 5 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 first purified by normal phase medium pressure preparation (EA: PE = 10-65%), and then purified by reverse phase medium pressure preparation (ACN: H2O = 5-55%), and lyophilized to obtain 4.9 mg of white solid compound 3. MS m / z (ESI): 531.18 [M+H] + .

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.54(s,1H),7.90(s,1H),7.65(d,J=8.2Hz,2H),7.53(d,J=8.2Hz ,2H),4.56(s,2H),3.84(s,3H),3.74(s,3H),1.68-1.59(m,1H),1.00-0.97(m,2H),0.90-0.75(m,2H).

[0126] Example 4 Preparation of Compound 4

[0127]

[0128] Step 1: Synthesis of compound 4-a

[0129] Compound 2-d (124.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (8 mL), N-chlorosuccinimide (40.1 mg, 0.30 mmol) was added, and the mixture was stirred at 70°C overnight. 10 mL of water was added, and the mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase medium pressure preparation (ACN:H2O=5–70%) and freeze-dried to obtain 56.0 mg of white solid 4-a. MS m / z(ESI):670.23[M+H] + .

[0130] Step 2: Synthesis of compound 4

[0131] Referring to the synthesis of compound 2, 2-d was replaced by 4-a. MS m / z (ESI): 540.14 [M+H] + .

[0132] 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),8.67(s,1H),7.91-7.88(m,1H),7.84(s,1H),7.63(d,J=8.2Hz,2H),7.49( d,J=8.2Hz,2H),4.63(s,2H),3.84(s,3H),3.74(s,3H),1.71-1.58(m,1H),1.07-0.98(m,2H),0.88-0.78(m,2H).

[0133] Example 5 Preparation of Compound 5

[0134]

[0135] Step 1: Synthesis of compound 5

[0136] Compound 22 (80.0 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (43.7 mg, 0.32 mmol) was added in batches under an ice-water bath, and iodomethane (33.7 mg, 0.24 mmol) was added after stirring at room temperature for half an hour. Then, it was stirred at room temperature for 4 hours. LC-MS monitored the completion of the reaction of the raw materials, poured the reaction solution into water, extracted with ethyl acetate (3*20 mL), washed with saturated brine 3 times, 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 medium-pressure reverse phase preparation (ACN:H2O=3:2), and vacuum-dried to obtain 50.0 mg of white solid compound 5. MS m / z (ESI): 520.05 [M+H] + .

[0137] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),7.93(d,J=1.1Hz,1H),7.87(d,J=3.1Hz,1H),7.68(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),6. 65(d,J=3.1Hz,1H),4.70(s,2H),4.08(s,3H),3.87(s,3H),3.78(s,3H),1.73-1.59(m,1H),1.10-0.94(m,2H),0.95-0.75(m,2H).

[0138] Example 6 Preparation of Compound 6

[0139]

[0140] Step 1: Synthesis of compound 6-b

[0141] Dissolve 6-a (3.0 g, 16.04 mmol) in dichloromethane (50 mL). Under nitrogen protection, add N-iodosuccinimide (5.4 g, 24.06 mmol) in an ice bath, stir at room temperature for 4 hours, add ice water (100 mL), filter, rinse the solid with petroleum ether, and concentrate under reduced pressure to obtain 4.7 g of compound 6-b. MS m / z (ESI): 310.9 [MH] - .

[0142] Step 2: Synthesis of compound 6-c

[0143] Referring to the synthesis of compound 2-b, 2-a was replaced by 6-b. MS m / z (ESI): 443.0 [M+H] + .

[0144] Step 3: Synthesis of compound 6-d

[0145] Under nitrogen protection, 6-c (2.0 g, 4.51 mmol) was dissolved in N-methylpyrrolidone (30 mL). Cuprous cyanide (0.8 g, 9.03 mmol) was added under ice bath and stirred at 120°C for 8 hours. After the reaction solution was cooled to room temperature, ice water (50 mL) was added, filtered, and the filtrate was extracted with ethyl acetate (2*50 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 subjected to silica gel column chromatography (PE:EA=30:1–5:1) to obtain 1.2 g of compound product 6-d.

[0146] Step 4: Synthesis of compound 6-e

[0147] Referring to the synthesis of compound 2-d, 2-c was replaced by 6-d. MS m / z (ESI): 456.0 [M+H] + .

[0148] Step 5: Synthesis of compound 6-f

[0149] Referring to the synthesis of compound 2-c, 2-b was replaced by 6-e. MS m / z (ESI): 660.0 [M+H] + .

[0150] Step 6: Synthesis of compound 6

[0151] Referring to the synthesis of compound 2, 2-d was replaced by 6-f. MS m / z (ESI): 530.1 [M+H] + .

[0152] 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),8.64(s,1H),8.50(s,1H),7.90(s,1H),7.68(d,J=8.2Hz,2H),7.49(d,J=8.2H z,2H),7.28(s,1H),4.53(s,2H),3.82(s,3H),3.76(s,3H),1.81-1.68(m,1H),1.08-0.98(m,2H),0.89-0.78(m,2H).

[0153] Example 7 Preparation of Compound 7

[0154]

[0155] Step 1: Synthesis of compound 7-a

[0156] Under nitrogen protection, 6-e (283.0 mg, 0.62 mmol), biboric acid pinacol ester (int-ag, 314.8 mg, 1.24 mmol), potassium acetate (182.6 mg, 1.86 mmol), tris [dibenzylideneacetone] palladium (56.8 mg, 0.06 mmol), tricyclohexylphosphine (34.8 mg, 0.12 mmol), dioxane (8 mL) were added to the reaction bottle and stirred at 100 ° C overnight. Filter, concentrate the filtrate under reduced pressure to obtain a crude product, and the crude product is chromatographed on a silica gel column (PE: EA = 20: 1–2: 1) to obtain 220.0 mg of compound 7-a. MS m / z (ESI): 548.29 [M+H] + .

[0157] Step 2: Synthesis of compound 7-b

[0158] 7-a (190.0 mg, 0.35 mmol), int-ce (128.7 mg, 0.38 mmol), tetratriphenylphosphine palladium (40.1 mg, 0.03 mmol), potassium carbonate (143.9 mg, 1.04 mmol), tetrahydrofuran (8 mL), water (2 mL) were added to the reaction flask, nitrogen protection, stirred at 80 ° C for 4 hours. 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 chromatographed on a silica gel column (PE:EA=20:1–1:1) to obtain 230.0 mg of compound 7-b. MS m / z(ESI):678.1[M+H] + .

[0159] Step 3: Synthesis of compound 7

[0160] Referring to the synthesis of compound 2, 2-d was replaced by 7-b. MS m / z (ESI): 548.2 [M+H] + .

[0161] 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),8.65(s,1H),8.51(s,1H),7.98(s,1H),7.56(t,J=7.8Hz,1H),7.39(d,J=11.3Hz, 1H),7.35-7.28(m,2H),4.56(s,2H),3.83(s,3H),3.58(s,3H),1.82-1.71(m,1H),1.09-0.98(m,2H),0.91-0.80(m,2H).

[0162] Example 8 Preparation of Compound 8

[0163]

[0164] Step 1: Synthesis of compound 8-b

[0165] Referring to the synthesis of compound 1-b, 1-a was replaced by 8-a. MS m / z (ESI): 272.67 [M+H] + .

[0166] Step 2: Synthesis of compound 8-c

[0167] 8-b (420.0 mg, 1.54 mmol) was dissolved in tetrahydrofuran (5 mL), LDA (1.54 mL, 3.08 mmol) was added dropwise at -78 °C, and stirred for 30 min. Iodomethane (0.25 mL, 3.08 mmol) was added, and the mixture was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3*10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, and separated and purified with a normal phase chromatography column (PE:EA=4:1) to obtain 200.0 mg of white solid 8-c. MSm / z(ESI):287.03[M+H] + .

[0168] Step 3-5: Synthesis of compound 8 with reference to compound 1. MS m / z (ESI): 521.19 [M+H] + .

[0169] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),7.89(d,J=1.4Hz,1H),7.62(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),4. 46(s,2H),3.83(s,3H),3.74(s,3H),2.61(s,3H),1.58-1.62(m,1H),0.97-1.04(m,2H),0.77-0.84(m,2H).

[0170] Example 9 Preparation of Compound 9

[0171]

[0172] Step 1: Synthesis of compound 9-a

[0173] Referring to the synthesis of compound 1-c, 1-b was replaced by 2-b, and int-af was replaced by int-ce. MS m / z(ESI):540.2[M+H] + .

[0174] Step 2: Synthesis of compound 9-b

[0175] Referring to the synthesis of compound 2-d, 2-c was replaced by 9-a. MS m / z (ESI): 654.3 [M+H] + .

[0176] Step 3: Synthesis of compound 9-c

[0177] Under nitrogen protection, compound 9-b (305.0 mg, 0.47 mmol) was dissolved in dimethyl sulfoxide (10 mL), N-iodosuccinimide (209.9 mg, 0.93 mmol) was added, and the mixture was reacted at 80°C for half an hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (2*15 mL). The organic phase was washed with saturated sodium thiosulfate, and then washed with saturated brine three times, 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 silica gel column chromatography (PE:EA=10:1–1:1) to obtain 298.0 mg of compound 9-c. MS m / z (E SI): 780.2 [M+H] + .

[0178] Step 4: Synthesis of compound 9-d

[0179] Referring to the synthesis of compound 3-b, 3-a was replaced by 9-c. MS m / z (ESI): 679.2 [M+H] + .

[0180] Step 5: Synthesis of compound 9

[0181] Referring to the synthesis of compound 3, 3-b was replaced by 9-d. MS m / z (ESI): 549.2 [M+H] + .

[0182] 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),8.68(s,1H),8.63(s,1H),7.97(d,J=0.9Hz,1H),7.55(t,J=7.8Hz,1H),7.44-7.37(m,1H ),7.37-7.31(m,1H),4.63(s,2H),3.85(s,3H),3.57(d,J=1.0Hz,3H),1.73-1.63(m,1H),1.08-0.99(m,2H),0.90-0.80(m,2H).

[0183] Example 10 Preparation of Compound 10

[0184]

[0185] Step 1: Synthesis of compound 10-b

[0186] Compound 10-a (4.0 g, 21.28 mmol) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (5.9 g, 42.55 mmol) was added at room temperature, stirred at room temperature for 0.5 h, iodomethane (4.5 g, 31.91 mmol) was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was added to ice water (200 mL), 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 4.1 g of white solid compound 10-b. MS m / z (ESI): 203.08 [M+H] + .

[0187] Step 2: Synthesis of compound 10-c

[0188] Under nitrogen protection, compound 10-b (165.5 mg, 0.82 mmol), int-h (300.0 mg, 0.82 mmol), potassium phosphate (347.8 mg, 1.64 mmol), bis(triphenylphosphine)palladium dichloride (57.5 mg, 0.08 mmol) were dissolved in toluene (9 mL) and water (3 mL), and stirred at 90 ° C overnight. Extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a normal phase chromatography column (PE:EA=4:1) to obtain 95.0 mg of white solid 10-c. MS m / z(ESI):406.13[M+H] + .

[0189] Step 3: Synthesis of compound 10

[0190] Under nitrogen protection, 10-c (95.0 mg, 0.23 mmol) was dissolved in 5 mL of dioxane, 1 mL of water, 1-d (45.4 mg, 0.23 mmol), Pd(dppf)Cl2 (17.1 mg, 0.02 mmol) and potassium carbonate (64.7 mg, 0.47 mmol) were added, and the mixture was stirred at 100°C overnight. After the reaction was completed, 50 mL of water was added to the mixture, and it was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by preparative method to obtain 18.0 mg of white solid compound 10. MS m / z (ESI): 520.21 [M+H] + .

[0191] 1H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.88(d,J=3.1Hz,1H),7.53(d,J=8.5Hz,2H),7.47(d,J=8.5Hz,2H),6.75(s,1H),6.65(d ,J=3.1Hz,1H),4.72(s,2H),4.09(s,3H),3.86(s,3H),2.33(s,3H),1.80-1.58(m,1H),1.08-0.98(m,2H),0.92-0.78(m,2H).

[0192] Example 11 Preparation of Compound 11

[0193]

[0194] Step 1: Synthesis of compound 11-a

[0195] Referring to the synthesis of compound 2-c, 2-b was replaced by 10-b and int-a was replaced by int-d. MS m / z (ESI): 452.13 [M+H] + .

[0196] Step 2: Synthesis of compound 11

[0197] Referring to the synthesis of compound 1-e, 1-c was replaced by 11-a. MS m / z (ESI): 566.21 [M+H] + .

[0198] 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.24 (s, 1H), 7.90 (d, J = 3.1Hz, 1H), 7. 52(t,J=7.8Hz,1H),7.39(d,J=11.2Hz,1H),7.31(d,J=8.1Hz,1H),6.66(d,J =3.1Hz,1H),4.74(s,2H),4.19-4.14(m,1H),4.13(s,3H),3.86(s,3H),1.7 4-1.59(m,1H),1.36(d,J=6.6Hz,6H),1.08-0.99(m,2H),0.93-0.62(m,2H).

[0199] Example 12 Preparation of Compound 12

[0200]

[0201] Step 1: Synthesis of compound 12-a

[0202] Referring to the synthesis of compound 2-c, int-a was replaced by int-b. MS m / z (ESI): 550.2 [M+H]+.

[0204] Step 2-5: Synthesis of compound 12 with reference to compound 9. MS m / z (ESI): 559.2 [M+H] + .

[0205] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),8.68(s,1H),8.62(s,1H),8.14(d,J=1.0Hz,1H),7.52(q,J=8.4Hz,4H),4.59(s ,2H),4.47-4.37(m,1H),3.84(s,3H),1.69-1.59(m,1H),1.38(d,J=6.6Hz,6H),1.07-0.98(m,2H),0.87-0.77(m,2H).

[0206] Example 13 Preparation of Compound 13

[0207]

[0208] Step 1: Synthesis of compound 13-a

[0209] Under nitrogen protection, compound 2-b (5.0 g, 15.71 mmol) and int-cg (1.5 g, 4.71 mmol) were dissolved in tetrahydrofuran (70 mL), and potassium bis(trimethylsilyl)amide (7.85 mL, 1 M) was added dropwise under ice bath, and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (2*50 mL), washed with saturated brine, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1–2:3) to obtain 2.1 g of compound 13-a. MS m / z(ESI):598.2[M+H] + .

[0210] Step 2: Synthesis of compound 13-b

[0211] Compound 13-a (2.0 g, 3.34 mmol) was dissolved in acetic acid (6 mL), concentrated hydrochloric acid (2 mL) was added, and stirred in a sealed tube at 80 ° C for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the pH was adjusted to 7-8 with sodium carbonate, extracted with ethyl acetate (2*50 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 silica gel column chromatography (PE:EA=10:1–1:1) to obtain 1.2 g of compound 13-b. MS m / z(ESI):409.9[M+H] + .

[0212] Step 3: Synthesis of compound 13-c

[0213] Referring to the synthesis of compound 1-e, 1-c was replaced by 13-b. MS m / z (ESI): 524.2 [M+H] + .

[0214] Step 4: Synthesis of compound 13

[0215] Under nitrogen protection, compound 13-c (150.0 mg, 0.29 mmol) was dissolved in acetonitrile (8 mL) and pyridine (2 mL), and a selective fluorine reagent (152.3 mg, 0.43 mmol) was added under ice bath, and stirred at room temperature overnight. Water (10 mL) was added, and ethyl acetate was extracted (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 medium pressure reverse phase preparation to obtain 17.3 mg of compound 13. MS m / z (ESI): 542.2 [M+H] + .

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 11.3 Hz, 1H), 7.33-7.28 (m, 1H), 4.51 (s, 2H), 3.84 (s, 3H), 3.57 (d, J = 1.2 Hz, 3H), 1.73-1.62 (m, 1H), 1.09-0.97 (m, 2H), 0.89-0.80 (m, 2H). Example 14 Preparation of Compound 14

[0217]

[0218] Step 1: Synthesis of compound 14-a

[0219] Under nitrogen protection, compound 9-c (100.0 mg, 0.13 mmol), trimethylcyclotriboroxane (96.6 mg, 0.77 mmol), potassium carbonate (53.2 mg, 0.38 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (9.4 mg, 0.01 mmol), dioxane (4 mL), and water (1 mL) were added to the reaction flask and stirred at 100°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=10:1–1:2) to obtain 43.0 mg of compound 14-a. MS m / z(ESI):668.3[M+H] + .

[0220] Step 2: Synthesis of compound 14

[0221] Referring to the synthesis of compound 2, 2-d was replaced by 14-a. MS m / z (ESI): 538.2 [M+H] + .

[0222] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.65(s,1H),7.97(d,J=0.9Hz,1H),7.52(t,J=7.8Hz,1H),7.37-7.32(m,2H),7.32-7.25 (m,1H),4.56(s,2H),3.84(s,3H),3.57(d,J=1.1Hz,3H),2.44(s,3H),1.74-1.63(m,1H),1.06-0.98(m,2H),0.87-0.78(m,2H).

[0223] Example 15 Preparation of Compound 15

[0224]

[0225] Step 1: Synthesis of compound 15-a

[0226] Under nitrogen protection, compound 3-a (45.0 mg, 0.06 mmol), trimethylsilyl acetylene (200 μL), bis(triphenylphosphine) palladium dichloride (8.4 mg, 0.01 mmol), cuprous iodide (7.6 mg, 0.02 mmol), and triethylamine (3 mL) were added to the reaction flask and stirred at 80°C overnight. Filter and concentrate the filtrate under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1–2:3) to obtain 34.0 mg of compound 15-a. MS m / z (ESI): 732.1 [M+H] +.

[0227] Step 2: Synthesis of compound 15-b

[0228] Compound 15-a (34.0 mg, 0.05 mmol) was dissolved in methanol (2 mL), potassium carbonate (20.7 mg, 0.15 mmol) was added, stirred at room temperature for 20 minutes, saturated brine (10 mL) 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 27.0 mg of compound 15-b. MS m / z (ESI): 660.2 [M+H] + .

[0229] Step 3: Synthesis of compound 15

[0230] Referring to the synthesis of compound 2, 2-d was replaced by 15-b. MS m / z (ESI): 530.2 [M+H] + .

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 4.67 (s, 2H), 4.39 (s, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 1.70-1.55 (m, 1H), 1.08-0.95 (m, 2H), 0.88-0.73 (m, 2H). Example 16 Preparation of Compound 16

[0232]

[0233] Step 1: Synthesis of compound 16-a

[0234] Under nitrogen protection, sodium hydride (1046.0 mg, 26.15 mmol) was added to dry tetrahydrofuran (10 mL), and a solution of 6-a (1630.0 mg, 8.72 mmol) in tetrahydrofuran (20 mL) was added under ice bath, and then triisopropylsilyl chloride (2.8 mL, 13.07 mmol) was added, and stirred at 80°C for 1 hour. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain 2.79 g of compound 16-a. MS m / z (ESI): 343.2 [M+H] + .

[0235] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=3.6Hz,1H),7.41(s,1H),6.72(d,J=3.6Hz,1H),1.85-1.77(m,3H),1.08-1.05(m,18H).

[0236] Step 2: Synthesis of compound 16-b

[0237] Under nitrogen protection, 16-a (2590.0 mg, 7.54 mmol) and N,N,N',N'-tetramethylethylenediamine (2.49 mL, 16.59 mmol) were dissolved in dry tetrahydrofuran (30 mL), and n-butyllithium n-hexane solution (10.37 mL, 16.59 mmol, 1.6 M) was slowly added dropwise at -78 ° C, stirred at -78 ° C for half an hour, and then diluted N-fluorobisbenzenesulfonamide (5945.2 mg, 18.86 mmol) tetrahydrofuran solution (40 mL) was added dropwise, and the mixture was naturally heated to room temperature and stirred for 18 hours. After the reaction was cooled to 0 ° C, it was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (3*100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3.05 g of crude compound 16-b.

[0238] Step 3: Synthesis of compound 16-c

[0239] Compound 16-b (3050.0 mg, 8.44 mmol) was dissolved in tetrahydrofuran (30 mL), tetrabutylammonium fluoride tetrahydrofuran solution (10.13 mL, 10.13 mmol) was added, and stirred at room temperature for 1 hour. Water (50 mL) was added, extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE: EA = 3: 1) to obtain 980.0 mg of compound 16-c. MS m / z (ESI): 205.1 [M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),7.75(dd,J=3.6,1.2Hz,1H),6.61(d,J=3.6Hz,1H). 19 F NMR(376MHz,DMSO-d6)δ-137.01.

[0241] Step 4: Synthesis of compound 16-d

[0242] Referring to the synthesis of compound 2-b, 2-a was replaced by 16-c. MS m / z (ESI): 335.2 [M+H] + .

[0243] Step 5: Synthesis of compound 16-e

[0244] Under nitrogen protection, 16-d (1060.0 mg, 3.16 mmol), 1-d (613.3 mg, 3.16 mmol), sodium carbonate (1005.3 mg, 9.48 mmol), tetrakistriphenylphosphine palladium (365.3 mg, 0.32 mmol), dioxane (30 mL) and water (6 mL) were added to the reaction flask and stirred at 80 ° C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE: EA = 3: 1) to obtain 806.0 mg of compound 16-e. MS m / z (ESI): 449.2 [M + H] + .

[0245] Step 6: Synthesis of compound 16-f

[0246] Referring to the synthesis of compound 7-a, 6-e was replaced by 16-e. MS m / z (ESI): 541.4 [M+H] + .

[0247] Step 7: Synthesis of compound 16-g

[0248] Referring to the synthesis of compound 7-b, 7-a was replaced by 16-f. MS m / z (ESI): 671.4 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.95(d,J=1.6Hz,1H),7.77(d,J=3.6Hz,1H),7 .52(t,J=8.0Hz,1H),7.34-7.23(m,2H),6.80(d,J=3.6Hz,1H),5.57(s,2H),4.44(s, 2H),3.83(s,3H),3.55(d,J=1.6Hz,3H),3.53-3.49(m,2H),1.76-1.67(m,1H),1.16 -1.08(m,1H),1.04-0.95(m,1H),0.91-0.82(m,2H),0.80-0.71(m,2H),0.18(s,9H).

[0250] Step 8: Synthesis of compound 16

[0251] Referring to the synthesis of compound 2, 2-d was replaced by 16-g. MS m / z (ESI): 541.23 [M+H] + .

[0252] 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.71 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 2.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 11.2 Hz, 1H), 7.33-7.26 (m, 1H), 6.73 (dd, J = 3.6, 1.6 Hz, 1H), 4.45 (s, 2H), 3.87 (s, 3H), 3.59 (d, J = 1.2 Hz, 3H), 1.81-1.71 (m, 1H), 1.17-1.09 (m, 1H), 1.07-1.00 (m, 1H), 0.96-0.85 (m, 2H). Example 17 Preparation of Compound 17

[0253]

[0254] Step 1: Synthesis of compound 17-a

[0255] Under nitrogen protection, compound 10-b (74.6 mg, 0.37 mmol), compound int-j (100.0 mg, 0.22 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (32.8 mg, 0.04 mmol), sodium carbonate (357.0 mg, 1.68 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (1 mL), stirred at 80°C for 3 hours, the reaction solution was added to water (10 mL), extracted with ethyl acetate (3*10 mL), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:2) gave 60.0 mg of compound 17-a. MS m / z(ESI):446.13[M+H] + .

[0256] Step 2: Synthesis of compound 17

[0257] Under nitrogen protection, compound 17-a (60.0 mg, 0.13 mmol), compound 1-d (31.3 mg, 0.16 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25.7 mg, 0.05 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (21.1 mg, 0.03 mmol), potassium phosphate (57.1 mg, 0.21 mmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.4 mL), stirred at 80° C. for 3 hours, and the reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-0:1) and then medium pressure reverse phase purification was performed to obtain 20.26 mg of compound 17. MS m / z(ESI):560.23[M+H] + .

[0258] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),7.96(d,J=1.2Hz,1H),7.86(d,J=3.2Hz,1H),7.65-7 .58(m,1H),7.32-7.24(m,2H),6.64(d,J=3.2Hz,1H),4.66(s,2H),4.08(s,3H),4.06-4.0 0(m,1H),3.86(s,3H),2.72-2.62(m,1H),2.51-2.44(m,1H),2.37-2.24(m,1H),2.07-1.9 7(m,1H),1.70-1.60(m,1H),1.46(d,J=6.8Hz,3H),1.10-1.01(m,2H),0.90-0.81(m,2H).

[0259] Example 18 Preparation of Compound 18

[0260]

[0261] Step 1: Synthesis of compound 18-a

[0262] Under nitrogen protection, compound int-i (300.0 mg, 0.76 mmol), 10-b (154.5 mg, 0.76 mmol), potassium phosphate (324.8 mg, 1.53 mmol), bis(triphenylphosphine)palladium dichloride (57.0 mg, 0.08 mmol) were dissolved in toluene (9 mL) and water (3 mL), and stirred at 90 ° C overnight. Extracted with ethyl acetate (3*20 mL), washed with saturated brine, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a normal phase chromatography column (PE:EA=4:1) to obtain 50.0 mg of white solid compound 18-a. MS m / z (ESI): 432.12 [M+H] + .

[0263] Step 2: Synthesis of compound 18

[0264] Under nitrogen protection, 18-a (50.0 mg, 0.12 mmol) was dissolved in 5 mL of dioxane, 1 mL of water, 1-d (22.5 mg, 0.12 mmol), Pd(dppf)Cl2 (9.1 mg, 0.01 mmol) and potassium carbonate (67.6 mg, 0.48 mmol) were added, and the mixture was stirred at 100°C overnight. After the reaction was completed, 50 mL of water was added to the mixture, and it was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by medium-pressure reverse phase preparation to obtain 7.0 mg of white solid compound 18. MS m / z (ESI): 546.41 [M+H] + .

[0265] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.88(d,J=3.1Hz,1H),7.61(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),6.65(d,J=3.1Hz,1H),6.63(s,1H),4 .73(s,2H),4.09(s,3H),3.85(d,J=5.8Hz,3H),1.91-1.74(m,1H),1.74 -1.57(m,1H),1.09-1.01(m,2H),0.99-0.91(m,2H),0.90-0.80(m,4H).

[0266] Example 19 Preparation of Compound 19

[0267]

[0268] Step 1: Synthesis of compound 19

[0269] Compound 22 (20.0 mg, 0.04 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), potassium hydroxide (26.6 mg, 0.47 mmol) was added at room temperature, and 19-a (21.1 mg, 0.08 mmol) was added after stirring at room temperature for 0.5 h, and the mixture was reacted overnight at room temperature. The reaction solution was added to water (20 mL), 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 2.0 mg of white solid compound 19. MS m / z (ESI): 556.31 [M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.32(d,J=3.6Hz,1H),8.10(t,J=59.2Hz,1H),7.93(d,J=1.1Hz,1H),7.65(d,J=8.3Hz,2H),7.42( d,J=8.3Hz,2H),7.00(d,J=3.6Hz,1H),4.67(s,2H),3.86(s,3H),3.77(s,3H),1.71-1.58(m,1H),1.06-0.99(m,2H),0.87-0.81(m,2H).

[0271] Example 20-57 Compound 20-57 was prepared by referring to the synthesis method of the above compound

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] KSQ-4279 and control compound A Prepared according to CN113164485A.

[0279] Example 58 Cell assay evaluation

[0280] 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. On 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 QueousOne 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.

[0281] Table 1 Inhibitory activity of the compounds of the present invention on MDA-MB-436 cells

[0282] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 49.5 2 9.9 3 22.8 4 14.3 5 7.6 6 8.3 7 6.3 8 23.5 9 30.6 10 5.9 11 5.4 12 22.3 13 6.8 14 7.3 15 9.6 16 3.4 17 5.7 18 7.2 19 8.0 20 42.1 21 16.6 22 10.3 23 34.3 24 32.8 25 10.3 26 8.4 27 12.8 28 19.6 29 2.9 30 1.8 31 4.0 32 8.7 33 5.7 34 4.2 35 8.2 36 12.6 37 4.6 38 5.5 40 5.1 41 8.5 42 14.0 43 15.3 44 9.8 45 5.8 46 5.1 47 4.4 48 5.0 49 3.1 50 5.2 51 5.5 52 9.6 53 3.5 54 4.0 55 8.8 56 5.5 57 13.9 KSQ-4279 <![CDATA[31.6 (n＝11) ]]>

[0283] As shown in Table 1, the compounds of the present invention have an effect on BRCA1 - / - MDA-MB-436 cells have a good inhibitory effect.

[0284] Example 59 Evaluation of metabolic stability of liver microsomes

[0285] Experimental materials: Human liver microsomes (purchased from BIOIVT, catalog number: X008070) were used in the experiment;

[0286] Reagent preparation:

[0287] PBS: 0.1 M KH2PO4 and K2HPO4 buffer, pH 7.4.

[0288] MgCl2: Weigh a certain amount of MgCl2 and prepare a 16 mM MgCl2 solution with PBS.

[0289] NADPH (Chinese name: reduced nicotinamide adenine dinucleotide phosphate, purchased from Sigma, catalog number: 481973-500mg): Weigh a certain amount of NADPH, and prepare NADPH to 4mM with 16mM MgCl2 solution, and the final incubation concentration is 1mM.

[0290] Compounds: The test compounds were prepared to 4 μM in PBS, and the final incubation concentration was 1 μM.

[0291] Liver microsomes: Dilute liver microsomes to 1 mg / mL with PBS, and the final incubation concentration is 0.5 mg / mL.

[0292] Experimental steps:

[0293] Add the prepared test compound to the test tube, then add the prepared NADPH and mix well. Pre-incubate in a 37°C, 220rpm constant temperature incubator. After pre-incubation for 5 minutes, add the prepared liver microsomes to start the reaction, and perform duplicate operations. At 0min, 15min, 30min, 45min, and 60min, add a certain volume of ice acetonitrile solution containing internal standard to the corresponding tube to precipitate protein, vortex for 5min, then centrifuge at 4000rpm for 10min, and take the supernatant in a 96-well plate. Put it into LC-MS / MS for analysis. The concentration (peak area ratio) of the example compound is determined by LC-MS / MS, and the rate constant is obtained by plotting "Ln (compound residual amount %)" against "incubation time" in Excel, thereby calculating the half-life and intrinsic clearance of the drug, providing a basis for the prediction of the in vivo clearance rate.

[0294] Data Analysis:

[0295] CL int =(0.693 / t 1 / 2 , microsomes) × [incubation fluid volume (mL) / microsomal protein mass (mg)] × [microsomal protein mass (mg) / liver mass (g)] × [liver mass (g) / body weight (kg)] [1]

[0296] CL H =CL int ×f u ×Q h / (CL int ×f u +Q h )

[0297] In the formula, CL int --Intrinsic clearance (mL / min / kg); CL H --Hepatic clearance (mL / min / kg); f u --The unbound fraction of plasma proteins is 1; Q h --Hepatic blood flow.

[0298] Table 2 Stability of human liver microsomes of the compounds of the present invention

[0299]

[0300]

[0301] [1]Davies B, Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993;10:1093-5.

[0302] As shown in Table 2, the stability of the compound of the present invention in human liver microsomes is better than that of the control compound A.

[0303] Example 60 Evaluation of UGT1A1 Inhibition

[0304] Experimental materials: Human liver microsomes (purchased from BIOIVT, catalog number: X008070) were used in the experiment;

[0305] Reagent preparation:

[0306] Tris-HCl: Dilute 1M Tris-HCl to 50mM with ultrapure water.

[0307] MgCl2 solution: Weigh a certain amount of MgCl2 and prepare a 40 mM MgCl2 solution with 50 mM Tris-HCl.

[0308] Alamethoxazole working solution: Weigh a certain amount of alamethoxazole (purchased from Aladdin, product number: A132913-25mg), add 50mM Tris-HCl solution to prepare 25μg / mL.

[0309] Human liver microsomes: Dilute human liver microsomes to 0.4 mg / mL with alamethicin working solution. The final incubation concentration of liver microsomes is 0.1 mg / mL.

[0310] UDPGA (Chinese name uridine 5'-diphosphoglucuronic acid, purchased from Sigma, catalog number: U5625-500mg): Weigh a certain amount of UDPGA, prepare UDPGA to 20mM with MgCl2 solution, and the final incubation concentration is 5mM.

[0311] Compounds: The test compounds were gradually prepared with methanol and 50 mM Tris-HCl to 120, 40, 12, 4, 1.2, 0.4, 0.12, and 0 μM, and the final incubation concentrations were 30, 10, 3, 1, 0.3, 0.1, 0.03, and 0 μM.

[0312] Substrate working solution: Estradiol was prepared to 80 μM using 50 mM Tris-HCl, and the final incubation concentration was 20 μM.

[0313] The content of organic solvent in the final incubation system does not exceed 1%.

[0314] Experimental steps:

[0315] Add the prepared substrate working solution to a 96-well plate, then add the prepared human liver microsome working solution, then add the test compound, mix well, and place in a 37°C constant temperature incubator for pre-incubation. After pre-incubation for 5 minutes, add the prepared UDPGA to start the reaction and incubate for 15 minutes. After the incubation, add the pre-cooled acetonitrile (containing 0.3% formic acid) solution containing the internal standard to terminate the reaction. After protein precipitation, vortex for 5 minutes, then centrifuge at 4000rpm for 10 minutes, and take the supernatant into a 96-well plate. The metabolites of the substrate are detected by LC-MS / MS method (peak area ratio). The residual activity of the enzyme and the half inhibitory concentration (IC) are calculated based on the detected content. 50 The concentration of the test substance and the corresponding residual activity percentage were fitted using a nonlinear model using Excel software. The concentration of the test substance that inhibited the formation of metabolites by 50% was the IC 50 value.

[0316] Data analysis: The activity of UGT1A1 enzyme was expressed as the amount of metabolite generated, and the percentage of residual activity of the enzyme was calculated as follows:

[0317] Residual enzyme activity (%) = (UGT1A1 enzyme subtype activity in the presence of the test substance / activity of the solvent control group) × 100%, the activity of the solvent control group (0 μM) is set as 100%

[0318] Table 3 Inhibitory activity of the compounds of the present invention on UGT1A1

[0319] Compound <![CDATA[IC 50 (uM)]]> Compound <![CDATA[IC 50 (uM)]]> KSQ-4279 2.9 Compound 5 19.9 Compound 18 9.8

[0320] As shown in Table 3, the inhibition of UGT1A1 by the compounds of the present invention is significantly weaker than that by KSQ-4279, indicating that the compounds of the present invention have little effect on bilirubin metabolism.

[0321] Example 61 Pharmacokinetic Evaluation in Mice

[0322] Experimental materials: The experimental animals were healthy adult BALB / c female mice (provided by Sichuan Weitonglihua Experimental Animal Technology Co., Ltd.);

[0323] Experimental process:

[0324] Dosing method and sample collection for mice: 60 μL of whole blood from the fundus venous plexus of BALB / c female mice was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration in the intravenous administration group and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration in the oral gavage administration group, and the blood was centrifuged at 5000 rpm and 4 °C for 6 min to obtain plasma.

[0325] Sample Analysis:

[0326] Take 10 μL of mouse plasma sample, add 190 μL of acetonitrile solution containing internal standard to precipitate protein, vortex for 10 minutes, then centrifuge at 4000 rpm for 10 minutes, take the supernatant in a 96-well plate. Put it into LC-MS / MS for analysis. The LC-MS / MS method is used to determine the drug concentration in the plasma of mice at different times after administration of the example compound, and calculate the relevant pharmacokinetic parameters, study the pharmacokinetic behavior of the compound in mice, and evaluate its pharmacokinetic characteristics.

[0327] Table 4 Pharmacokinetic parameters of the test compounds in mouse plasma

[0328] Compound Dosage <![CDATA[Cmax(ng.mL -1 )]]> <![CDATA[AUC last (h.ng.mL -1 )]]> F(％) KSQ-4279 vein - 2865±678 - KSQ-4279 Oral gavage 1280±36 13637±990 49.3±5.0 Compound 3 vein - 4510±934 - Compound 3 Oral gavage 6147±1239 29989±8701 66.1±19.1 Compound 5 Oral gavage 3033±410 57490±4822 - Compound 10 Oral gavage 7317±405 90177±15432 - Compound 17 Oral gavage 4743±954 38834±12969 - Compound 20 vein - 5722±214 - Compound 20 Oral gavage 7323±1498 34649±6733 59.8±11.2

[0329] Note: For intravenous administration, the solvent is 5% DMSO + 5% solutol + 90% saline, and the dosage is 1 mg / kg; for oral administration, the solvent is 0.5% CMC-Na / 0.2% Tween 80, and the dosage is 10 mg / kg. DMSO: dimethyl sulfoxide; solutol: polyethylene glycol-15-hydroxystearate; saline: physiological saline; CMC-Na: sodium carboxymethylcellulose; Tween: Tween 80.

[0330] As shown in Table 4, the compound of the present invention has good oral absorption performance, and both intravenous injection and oral performance are better than KSQ-4279.

Claims

1. A compound of 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, CH; X2 is selected from O, S, N, CH, CH2, NR1; X3 is selected from N, NH, C=O, CR2, C(R2')(R2"); X4 is selected from O, S, N, NR1, CR3, C(R3')(R3"); R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl; R2 and R3 are each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; R2', R2", R3' and R3" are each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogen, -CN; or R3' and R3" are combined with the carbon atom to which they are attached to form C 3-6 Cycloalkyl; or R2' and R2" are combined with the carbon atom to which they are attached to form C 3-6 Cycloalkyl; R m and R n Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and at least 1 heteroatom is N; Each R g are each independently selected from -C(O)R i 、-C(O)NR i R j , C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy; L is selected from C(R4)(R5), O, S or Se; 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; 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 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; represents a single bond or a double bond, and the two Not a double bond at the same time.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, selected from the structure shown in formula IIa, IIb, IIc, IId, IIe or IIf: Or, selected from the structure shown in formula IIg: Preferably, R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R1 is selected from H, methyl, isopropyl, -CF3, -CHF2, -CH2CH2F, cyclopropyl; Or, selected from the structure shown in formula IIIa, IIIb, IIIc or IIId: Preferably, R3 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 1-4 Halogenated alkoxy, C 5-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-4 Alkenyl, C 5-6 Alkenyl, C 2-4 Alkynyl, C 5-6 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoroisobutyl, fluoro-tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, fluoro-n-butoxy, fluoro-sec-butoxy, fluoroisobutoxy, fluorotert-butoxy, F, Cl, Br, -CN, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR m R n ; Preferably, R3 is selected from H, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, fluoromethoxy, fluoroethoxy, F, Cl, Br, -CN, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR m R n ; Preferably, R3 is selected from H, methyl, -CF3, methoxy, -OCF3, -OCHF2, F, Cl, -CN, cyclopropyloxy, ethynyl, cyclopropyl, -NR m R n ; R m and R n Each independently selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and at least 1 heteroatom is N; Preferably, R m and R n Each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, -C 1-2 Alkyl-C 1-2 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, and at least 1 heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, ethyl, fluoromethyl, fluoroethyl, -C 1-2 Alkyl-methoxy, -C 1-2 Alkyl-ethoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g A substituted 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g A substituted 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, or R m and R n The N to which they are attached forms azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, Each R g Each independently selected from C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy; Preferably, each R g Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy; Preferably, each R g each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, -C 1-2 Alkyl-C 1-2 Alkoxy; Preferably, each R g Each independently selected from methyl, ethyl, fluoromethyl, fluoroethyl, -C 1-2 Alkyl-methoxy, -C 1-2 Alkyl-ethoxy; Preferably, each R g Each independently selected from methyl, Preferably, R3 is selected from H, methyl, -CF3, methoxy, -OCF3, -OCHF2, F, Cl, -CN, cyclopropyloxy, ethynyl, cyclopropyl, -NH2, Or, selected from the structure shown in formula Va, Vb, Vc or Vd: Preferably, R2 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, halogen; Preferably, R2 is selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen; Preferably, R2 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, F, Cl, Br; Preferably, R2 is selected from H, methyl, methoxy, F, Cl; Preferably, Selected from 3. A bicyclic compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof: Selected from the structure represented by formula VIa, VIb, VIc, VId or VIe; Or, selected from the structure shown in Formula VIIa or VIIb: Or, selected from the structure shown in formula VIIIa, VIIIb or VIIIc: in, Each R1 is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl; Each R2 and R3 are independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Acyl, -NR m R n ; Each R m and R n Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and at least 1 heteroatom is N; Each R g are each independently selected from -C(O)R i 、-C(O)NR i R j , C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy; Each L is independently selected from C(R4)(R5), O, S or Se; Each R4 and R5 are 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; Each ring A is independently 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; Each B is independently 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; Each 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; Each C is independently 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 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; Preferably, R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R1 is selected from H, methyl, isopropyl, -CF3, -CHF2, -CH2CH2F, cyclopropyl; or, Preferably, R3 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 1-4 Halogenated alkoxy, C 5-6 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-4 Alkenyl, C 5-6 Alkenyl, C 2-4 Alkynyl, C 5-6 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -CN, -OC 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, -NR m R n ; Preferably, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoroisobutyl, fluoro-tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, fluoro-n-butoxy, fluoro-sec-butoxy, fluoroisobutoxy, fluorotert-butoxy, F, Cl, Br, -CN, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR m R n ; Preferably, R3 is selected from H, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, fluoromethoxy, fluoroethoxy, F, Cl, Br, -CN, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR m R n ; Preferably, R3 is selected from H, methyl, -CF3, methoxy, -OCF3, -OCHF2, F, Cl, -CN, cyclopropyloxy, ethynyl, cyclopropyl, -NR m R n ; R m and R n Each independently selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and at least 1 heteroatom is N; Preferably, R m and R n Each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, -C 1-2 Alkyl-C 1-2 Alkoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, and at least 1 heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, ethyl, fluoromethyl, fluoroethyl, -C 1-2 Alkyl-methoxy, -C 1-2 Alkyl-ethoxy; or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g A substituted 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, or R m and R n The N to which they are attached is unsubstituted or substituted with one or more R g A substituted 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N; Preferably, R m and R n Each independently selected from H, methyl, or R m and R n The N to which they are attached forms azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, Each R g Each independently selected from C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy; Preferably, each R g Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy; Preferably, each R g each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoro-isopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoro-isobutyl, fluoro-tert-butyl, -C 1-2 Alkyl-C 1-2 Alkoxy; Preferably, each R g Each independently selected from methyl, ethyl, fluoromethyl, fluoroethyl, -C 1-2 Alkyl-methoxy, -C 1-2 Alkyl-ethoxy; Preferably, each R g Each independently selected from methyl, Preferably, R3 is selected from H, methyl, -CF3, methoxy, -OCF3, -OCHF2, F, Cl, -CN, cyclopropyloxy, ethynyl, cyclopropyl, -NH2, or, Preferably, R2 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, halogen; Preferably, R2 is selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen; Preferably, R2 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, F, Cl, Br; Preferably, R2 is selected from H, methyl, methoxy, F, Cl.

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: 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 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: 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, C 7-8 Cycloalkyl 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 Cycloalkyl, C 7-8 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 ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, The ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl are each independently unsubstituted or substituted by one or more identical or different halogens; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, The ethynyl, phenyl, pyridyl, pyrimidyl, cyclohexyl, piperidyl are each independently unsubstituted or substituted by one or more identical or different F, Cl or Br; Preferably, B is selected from phenyl, fluorophenyl, pyridyl, pyrimidyl, cyclohexyl, piperidyl, fluoropiperidyl, ethynyl, Preferably, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl, ethynyl, Preferably, B is selected from Ethylene, Preferably, B is selected from Ethylene, 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; Preferably, C is selected from Preferably, C is selected from 6. A 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, selected from the following structures:

7. A compound of formula (X), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof: in, X1 is selected from N, CH or CF, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3; Ring A is selected from Each R b Each is independently selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R c and R d The 6-8 membered heterocycloalkyl group is combined with the atoms to which it is attached to form a 6-8 membered heterocycloalkyl group, wherein the 6-8 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N; the 6-8 membered heterocycloalkyl group is unsubstituted or replaced by C 1-4 Alkyl substitution.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or 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.

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