Aryl and pyridone compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an aryl and pyridone compound as well as a preparation method and application thereof. The pharmaceutical composition comprises a compound shown in a general formula I and pharmaceutically acceptable salts thereof. The BET small-molecule inhibitor with selectivity to BD2 is novel in structure and good in BD2 selectivity and can be used for treating cancers.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to an arylpyridone compound and a preparation method and application thereof. Background Art

[0002] The bromodomain and extra-terminal (BET) protein family is a highly conserved protein family consisting of four members: BRD2, BRD3, BRD4, and BRDT. Each member contains two tandem bromodomains (BD1 and BD2). These eight bromodomains can specifically recognize acetylated lysine in histones, regulate the transcription of downstream genes, and participate in various biological processes such as cell growth, proliferation, differentiation, apoptosis, and necrosis. They are closely related to various human diseases (such as cancer, inflammation, and antiviral effects) and are potential drug targets.

[0003] Currently, many BET small molecule inhibitors have been reported to have excellent efficacy in cancer and inflammation, and many have entered the clinical stage. However, most of these BET small molecule inhibitors are pan-inhibitors, which have inhibitory effects on both BD1 and BD2 bromodomains, which leads to obvious dose-limiting toxicities of BET inhibitors in clinical practice (such as thrombocytopenia, gastrointestinal mucosal damage, hepatotoxicity, cardiotoxicity, etc.). AbbVie disclosed a class of BET inhibitors that are selective for BD2 in WO2017177955A1, among which the compound ABBV-744 showed outstanding efficacy and higher safety in preclinical studies. The compound has now entered the clinical stage.

[0004] In summary, the development of new, highly efficient, low-toxic BD2-selective BET small molecule inhibitors has better application prospects. Summary of the Invention

[0005] Purpose of the invention: In order to solve the dose-limiting toxicity problem of existing pan-BET inhibitors, the present invention provides a BD2-selective BET small molecule inhibitor, which provides possibilities for the subsequent development of anti-cancer drugs.

[0006] The technical solutions of the present invention are as follows:

[0007] An arylpyridone compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, has the following structure:

[0008]

[0009] in,

[0010] R 1 is H or halogen;

[0011] R 2 independently selected from hydrogen, C1-C3 alkyl, CH2-R 4 、COR 4 ;

[0012] X is N or CH;

[0013] R 3 Selected from R 4 Independently selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl group is optionally replaced by one or more R a Substitution; wherein R a Independently selected from methyl and hydroxy.

[0014] Preferably, the arylpyridone compound as shown in Formula I or a pharmaceutically acceptable salt thereof is characterized in that the compound is any one of the following compounds:

[0015]

[0016]

[0017] The aryl pyridone compound or its pharmaceutically acceptable salt is characterized in that the pharmaceutically acceptable salt is an acid addition salt formed by the compound with the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, fumaric acid, p-toluenesulfonic acid or ferulic acid.

[0018] The preparation method of the aryl pyridones is characterized in that the synthesis route of the compound is as follows:

[0019]

[0020] Wherein, X is NH or C, wherein R 1 、R 2 and R 3 Consistent with the definition in Formula I, the specific synthesis steps are as follows:

[0021] (1) Compound II-1 and II-2 are reacted by Suzuki reaction to obtain compound I;

[0022] or

[0023] (2) Compound II-3 and II-4 are reacted by Suzuki reaction to obtain compound I.

[0024] Specifically, under nitrogen protection, II-1 (1 eq), II-2 (1.2 eq), Pd(dppf)Cl2 (2 mol%), and 2.0 eq of potassium carbonate were placed in a sealed tube with a magnetic stirrer, 1,4-dioxane and water were added in a ratio of 5:1, and the mixture was reacted at 85°C for 12 h to obtain product I. Alternatively, under nitrogen protection, II-3 (1.2 eq), II-4 (1 eq), Pd(dppf)Cl2 (2 mol%), and 2.0 eq of potassium carbonate were placed in a sealed tube with a magnetic stirrer, 1,4-dioxane and water were added in a ratio of 5:1, and the mixture was reacted at 85°C for 12 h to obtain product I. Note: 1,4-dioxane is a solvent.

[0025] The Suzuki reaction, also known as the Suzuki-Miyaura coupling reaction, is an important organic coupling reaction that cross-couples aryl or alkenyl boronic acids (or boronic esters) with aryl or alkenyl halides (or quasi-halides, such as trifluoromethanesulfonates) using a palladium catalyst to form a new carbon-carbon bond (C-C bond).

[0026] A pharmaceutical composition, characterized in that it comprises the compound and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0027] Application of the arylpyridone compound or its pharmaceutically acceptable salt and the pharmaceutical composition in the preparation of a BET inhibitor.

[0028] Application of the arylpyridone compound or its pharmaceutically acceptable salt and the pharmaceutical composition in the preparation of drugs for treating cancer.

[0029] Application of the arylpyridone compound or its pharmaceutically acceptable salt and the pharmaceutical composition in the preparation of drugs for treating leukemia.

[0030] Beneficial effects

[0031] The present invention provides a class of small molecule BET inhibitors with selective BD2 inhibition. These inhibitors have novel structures and excellent BD2 selectivity, exceeding that of the clinical compound ABBV-744. The present invention also provides drugs that can be used to treat cancer. The compounds of the present invention have low toxicity to normal healthy cells and a high therapeutic safety window. The present invention also discloses a method for preparing the compound of Formula I. DETAILED DESCRIPTION

[0032] In order to better understand the present invention, the present invention is further illustrated by the following examples, but the content of the present invention is not limited to the following examples.

[0033] Example 1: Compound I-1

[0034] Synthesis route

[0035]

[0036] Step 1: Synthesis of compound I-1b

[0037] Compound I-1a (5.0 g, 18.65 mmol, 1.0 eq) and potassium carbonate (5.1 g, 37.31 mmol, 2.0 eq) were placed in a 100 mL round-bottom flask equipped with a magnetic stirrer. 40 mL of acetonitrile was added and stirred at room temperature. 1.74 mL of iodomethane (4.0 g, 28.0 mmol, 1.5 eq) was slowly added dropwise to the reaction system using a syringe. After complete addition, the mixture was allowed to react at room temperature for 3 h. TLC confirmed the complete reaction of the starting materials. The reaction mixture was filtered through celite, and the filter cake was rinsed with ethyl acetate. 100 mL of ethyl acetate and 10 mL of saturated sodium chloride were then added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 20:1 PE / EA) to afford the target compound I-1b (3.94 g, 75% yield). 1 H NMR (300MHz, CDCl3) δ9.29 (d, J = 2.4Hz, 1H), 8.52 (dd, J = 8.9, 2.4Hz, 1H), 7.97 (d, J = 8.9Hz, 1H), 7.57 (s, 1H), 3.66 (s, 3H).

[0038] Step 2: Synthesis of compound I-1c

[0039] Compound I-1b (3.5 g, 12.4 mmol, 1.0 eq), ammonium chloride (3.98 g, 74.4 mmol, 6.0 eq), and stannous chloride (7.1 g, 37.2 mmol, 3.0 eq) were placed in a 100 mL round-bottom flask with a magnetic stirrer. 40 mL of methanol was added, a reflux tube was inserted, and the reaction was carried out at 60°C for 12 h. TLC monitored the complete reaction of the starting materials. Saturated sodium carbonate solution was added dropwise to the reaction solution to adjust the pH to 7-8, and then the methanol was removed. 100 mL of ethyl acetate was added, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the target compound I-1c (2.12 g, yield 68%) was purified by column chromatography (200-300 mesh silica gel, 5:1 PE / EA). 1H NMR (300MHz, CDCl3) δ7.65(d,J=2.5Hz,1H),7.63(d,J=8.6Hz,1H),7.14(s,1H),7.08(dd,J=8.6,2.5Hz,1H),4.07(s,2H),3.57(s,3H).

[0040] Step 3: Synthesis of Compound I-1

[0041] Under nitrogen, compound I-1c (126.0 mg, 0.5 mmol, 1.0 eq), compound I-1d (153.0 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2 (7.3 mg, 2 mmol%), and potassium carbonate (138.0 mg, 1.0 mmol, 2.0 eq) were placed in a 15 mL sealed tube equipped with a magnetic stirrer. 2 mL of 1,4-dioxane and 0.4 mL of water were added, and the mixture was reacted at 85°C for 12 h. TLC confirmed the complete reaction of the starting materials. After the reaction solution cooled to room temperature, 20 mL of ethyl acetate was added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the target compound I-1 (139.1 mg, 65% yield) was purified by column chromatography (200-300 mesh silica gel, 30:1 CHCl2 / MeOH). 1 H NMR(300MHz, CDCl3)δ7.79(d,J=2.6Hz,1H),7.43(d,J=2.5Hz,1H),7.36–7.27(m,2H),7.0 8–6.98(m,4H),6.96(s,1H),6.38(d,J=8.6Hz,1H),3.65(s,3H),2.04(s,6H),1.59(s,6H).

[0042] Example 2: Compound I-2

[0043] Synthesis route

[0044]

[0045] Step 1: Synthesis of compound I-2b

[0046] Compound I-2a (2.0 g, 8.0 mmol, 1.0 eq), methylamine hydrochloride (2.16 g, 32.0 mmol, 4.0 eq), EDCI (1.68 g, 8.8 mmol, 1.1 eq), HOBt (1.19 g, 8.8 mmol, 1.1 eq), and DIPEA (5.16 g, 40.0 mmol, 5.0 eq) were placed in a 120 mL sealed tube with a magnetic stirrer, and 20 mL of DMF was added. The reaction solution was stirred at room temperature for 12 h. TLC monitored the complete reaction of the starting materials. 100 mL of ethyl acetate was added, and the mixture was washed five times with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (200-300 mesh silica gel, 5:1 PE / EA) to obtain the target compound I-2b (1.32 g, 63% yield). 1 H NMR (300MHz, CDCl3) δ8.77 (s, 1H), 7.63 (t, J = 5.1Hz, 1H), 3.02 (d, J = 5.1Hz, 3H), 2.58 (s, 3H).

[0047] Step 2: Synthesis of compound I-2c

[0048] Under nitrogen, compound I-2b (1.3 g, 5.0 mmol, 1.0 eq), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (1.48 g, 7.5 mmol, 1.5 eq), sodium carbonate (1.32 g, 12.5 mmol, 2.5 eq), and Pd(dppf)Cl2 (36.6 mg, 1 mmol%) were placed in a 120 mL sealed tube equipped with a magnetic stirrer. 25 mL of 1,4-dioxane and 5 mL of water were added, and the mixture was reacted at 95°C for 12 h. TLC confirmed the complete reaction of the starting materials. After the reaction mixture cooled to room temperature, it was filtered through celite, and the filter cake was rinsed with ethyl acetate. 50 mL of ethyl acetate was added, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed five times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 2:1 PE / EA) to give compound I-2c (746.4 mg, yield 59%). 1 HNMR (300MHz, CDCl3) δ8.69 (s, 1H), 7.98 (t, J = 5.1Hz, 1H), 6.99 (s, 2H), 3.99 (q,J=7.0Hz,2H),2.99(d,J=5.1Hz,3H),2.58(s,3H),1.36(t,J=7.0Hz,3H).

[0049] Step 3: Synthesis of compound I-2d

[0050] Under nitrogen, compound I-2c (500.0 mg, 2.0 mmol, 1.0 eq) and p-toluenesulfonic acid (102.0 mg, 0.6 mmol, 0.3 eq) were placed in a 15 mL sealed tube equipped with a magnetic stirrer. 6 mL of anhydrous toluene was added, and the mixture was allowed to react at 90°C for 2 h. TLC confirmed the complete reaction. After the reaction mixture cooled to room temperature, 30 mL of ethyl acetate and 5 mL of saturated sodium chloride solution were added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 40:1 CHCl / MeOH) to afford compound I-2d (343.6 mg, 83% yield). 1 H NMR (300MHz, CDCl3) δ8.93 (s, 1H), 7.17 (d, J = 7.2Hz, 1H), 6.43 (d, J = 7.2Hz, 1H), 3.66 (s, 3H), 2.71 (s, 3H).

[0051] Step 4: Synthesis of compound I-2e

[0052] Under nitrogen, compound I-2d (340 mg, 1.64 mmol, 1.0 eq) was placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 10 mL of anhydrous acetonitrile was added and stirred at room temperature. Solid NBS (321.1 g, 1.8 mmol, 1.1 eq) was added to the reaction system in three portions. After the addition was complete, the reaction system was stirred at room temperature for 12 h. TLC confirmed the complete reaction of the starting materials. 30 mL of ethyl acetate and 5 mL of saturated sodium chloride solution were added. The organic phase was separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed five times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 40:1 CHCl / MeOH) to afford compound I-2e (364.6 mg, 78% yield). 1 H NMR (300MHz, CDCl3) δ9.13(s,1H),7.37(s,1H),3.66(s,3H),2.72(s,3H).

[0053] Step 5: Synthesis of Compound I-2f

[0054] Compound I-2e (360.0 mg, 1.26 mmol, 1.0 eq) was placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 8 mL of anhydrous dichloromethane was added and stirred at room temperature. Solid m-chloroperbenzoic acid (654.1 mg, 3.79 mmol, 3.0 eq) was added to the reaction system in three portions. After the addition was complete, the reaction system was stirred at room temperature for 12 h. TLC confirmed the complete reaction of the starting material. 20 mL of dichloromethane and 5 mL of saturated sodium chloride solution were added. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed three times with saturated sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, it was purified by column chromatography (200-300 mesh silica gel, 1:1 PE / EA) to afford compound I-2f (276.3 mg, 69% yield). 1 H NMR (300MHz, CDCl3) δ9.57(s,1H),7.69(s,1H),3.73(s,3H),3.52(s,3H).

[0055] Step 6: Synthesis of Compound I-2g

[0056] Compound I-2f (269.5 mg, 0.85 mmol, 1.0 eq) was placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 3 mL of isopropanol was added and stirred at room temperature. 2 mL of concentrated aqueous ammonia was then slowly added dropwise to the reaction system. After addition, solid precipitation was observed. Stirring was continued at room temperature for 1 h. TLC confirmed the complete reaction of the starting material. The reaction mixture was filtered and the filter cake was rinsed with isopropanol. The filter cake was then dried by infrared spectroscopy to yield compound I-2g (181.4 mg, 84% yield). 1 H NMR (300MHz, DMSO-d6) δ8.83(s,1H),7.64(s,1H),6.72(s,2H),3.46(s,3H).

[0057] Step 7: Synthesis of Compound I-2

[0058] Referring to the synthesis method of compound I-1, the target compound I-2 (36.3 mg, yield 58%) was successfully obtained. 1 HNMR (300MHz, CDCl3) δ8.70 (s, 1H), 7.48 (d, J = 2.4Hz, 1H), 7.36 (dd, J = 8.6, 2.4Hz, 1H), 6.99 (s, 1H), 6.76 (d,J=8.8Hz,2H),6.40(d,J=8.6Hz,1H),5.62(s,2H),3.70(s,3H),2.05(s,6H),1.63(s,1H),1.61(s,6H).

[0059] Example 3: Compound I-3

[0060] Synthesis route

[0061]

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

[0063] Under nitrogen, compound I-1c (292.5 mg, 0.76 mmol, 1.0 eq) was placed in a 15 mL sealed tube equipped with a magnetic stirrer. 2 mL of anhydrous DMF was added for dissolution and stirred at 0°C for 5 min. Solid sodium hydride (45.6 mg, 1.14 mmol, 1.5 eq, 60%) was added to the reaction system. After addition, the reaction system was stirred at 0°C for 30 min. 0.12 mL of iodoethane (237.1 mg, 1.52 mmol, 2.0 eq) was slowly added dropwise to the reaction system via syringe. After addition, the reaction system was heated to 50°C and stirred for 3 h. TLC confirmed the complete reaction of the starting material. Saturated ammonium chloride solution was added dropwise under ice to quench the reaction. 30 mL of ethyl acetate was added. The organic phase was separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed five times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 2:1 PE / EA) to give compound I-3a (93.6 mg, yield 44%). 1 H NMR (300MHz, CDCl3) δ7.61(d,J=8.7Hz,1H),7.51(d,J=2.6Hz,1H),7.11(s,1H),7.0 1(dd,J=8.7,2.6Hz,1H),3.58(s,3H),3.29(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).

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

[0065] Referring to the synthesis method of compound I-1, the target compound I-3 (53.7 mg, yield 55%) was successfully obtained. 1HNMR (300MHz, CDCl3) δ7.59(d,J=2.6Hz,1H),7.43(d,J=2.5Hz,1H),7.26(d,J=8.6Hz,1H),7.07–6.95(m,3H),6.93(d,J=1.1Hz,1H),6 .91(d,J=8.6,2.6Hz,1H),6.38(d,J=8.6Hz,1H),3.65(s,3H),3.29(q,J=7.1Hz,2H),2.04(s,6H),1.60(s,6H),1.29(t,J=7.1Hz,3H).

[0066] Example 4: Compound I-4

[0067] Synthesis route

[0068]

[0069] Step 1: Synthesis of compound I-4a

[0070] Referring to the synthesis method of compound I-3a, the target compound I-4a (148.8 mg, yield 44%) was successfully obtained. 1 HNMR (300MHz, CDCl3) δ7.61(d,J=8.7Hz,1H),7.49(d,J=2.6Hz,1H),7.11(s,1H),7.03(dd,J=8.8,2.6Hz,1H ),4.23(s,1H),3.57(s,3H),3.09(d,J=7.0Hz,2H),1.20–1.03(m,1H),0.63–0.52(m,2H),0.33–0.23(m,2H).

[0071] Step 2: Synthesis of compound I-4

[0072] Referring to the synthesis method of compound I-1, the target compound I-4 (53.8 mg, yield 57%) was successfully obtained. 1 HNMR (400MHz, CDCl3) δ7.60(d,J=2.5Hz,1H),7.45(d,J=2.5Hz,1H),7.32(dd,J=8.6,2.5Hz,1H),7.27(d,J=8.2Hz,1H),7.08–6.89(m,5H),6.37(d, J=8.6Hz,1H),3.63(s,3H),3.07(d,J=6.9Hz,2H),2.04(s,6H),1.59(s,6 H),1.23(s,1H),1.16–1.05(m,1H),0.58–0.47(m,2H),0.29–0.19(m,2H).

[0073] Example 5: Compound I-5

[0074] Synthesis route

[0075]

[0076] Step 1: Synthesis of compound I-5a

[0077] Compound I-2f (111.0 mg, 0.35 mmol, 1.0 eq), cyclopropylmethylamine (37.3 mg, 0.53 mmol, 1.5 eq), and DIPEA (90.3 mg, 0.70 mmol, 2.0 eq) were placed in a 15 mL sealed tube equipped with a magnetic stirrer. 2 mL of anhydrous DMF was added for dissolution, and the mixture was stirred at 40°C for 12 h. TLC confirmed the complete reaction of the starting materials. 30 mL of ethyl acetate and 5 mL of saturated sodium chloride solution were added. The organic phase was separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed five times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, purification by column chromatography (200-300 mesh silica gel, 40:1 CH2Cl2 / MeOH) afforded compound I-5a (76.5 mg, 71% yield). 1 HNMR (300MHz, CDCl3) δ8.95(s,1H),7.09(s,1H),3.60(s,3H),3.47–3.37(m,2H),1.16–1.05(m,1H),0.55–0.50(m,2H),0.33–0.23(m,2H).

[0078] Step 2: Synthesis of compound I-5

[0079] Referring to the synthesis method of compound I-1, the target compound I-5 (44.1 mg, yield 56%) was successfully obtained. 1 HNMR(300MHz, CDCl3)δ8.68(s,1H),7.46(d,J=2.4Hz,1H),7.32(dd,J=8.6,2.4Hz,1H),7.12–6.96(m,3H),6.94(s,1H),6.39(d,J=8.6Hz,1H), 5.71(s,1H),3.67(s,3H),3.49–3.31(m,2H),2.04(s,6H),1.86(s,1H) ,1.60(s,6H),1.15–0.98(m,1H),0.58–0.45(m,2H),0.32–0.19(m,2H).

[0080] Example 6: Compound I-6

[0081] Synthesis route

[0082]

[0083] Step 1: Synthesis of compound I-6a

[0084] Under nitrogen, compound I-1c (400.0 mg, 1.58 mmol, 1.0 eq) and NEt3 (478.7 mg, 4.74 mmol, 3.0 eq) were placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 8 mL of anhydrous dichloromethane was added for dissolution and the mixture was stirred at room temperature. 0.17 mL of cyclopropylcarbonyl chloride (198.1 mg, 1.89 mmol, 1.2 eq) was slowly added dropwise to the reaction system. After complete addition, the reaction system was stirred at room temperature for 4 h. TLC confirmed the complete reaction of the starting materials. 10 mL of dichloromethane and 5 mL of saturated sodium chloride solution were added. The organic phase was separated, the aqueous phase extracted twice with dichloromethane, and the combined organic phases washed three times with saturated sodium chloride solution. Finally, purification by column chromatography (200-300 mesh silica gel, 40:1 CHCl / MeOH) afforded compound I-6a (203.0 mg, 40% yield). 1 H NMR (300MHz, CDCl3) δ8.46 (dd, J=8.9, 2.3Hz, 1H), 8.18 (d, J=2.3Hz, 1H), 7.77 (d, J=8.9Hz ,1H),7.29(s,1H),3.60(s,3H),1.72–1.58(m,1H),1.16–1.06(m,2H),0.92–0.83(m,2H).

[0085] Step 2: Synthesis of Compound I-6

[0086] Referring to the synthesis method of compound I-1, the target compound I-6 (35.2 mg, yield 65%) was successfully obtained. 1 HNMR(300MHz,DMSO-d6)δ10.53(s,1H),8.55(d,J=2.3Hz,1H),7.94(dd,J=8.8, 2.4Hz,1H),7.46(d,J=2.4Hz,1H),7.38(dd,J=8.6,2.4Hz,1H),7.30(d,J=8.8H z,1H),7.14–7.08(m,2H),7.07–7.00(m,1H),6.27(d,J=8.6Hz,1H),5.01(s,1H ),3.59(s,3H),1.98(s,6H),1.87–1.72(m,1H),1.44(s,6H),0.88–0.77(m,4H).

[0087] Example 7: Compound I-7

[0088] Synthesis route

[0089]

[0090] Step 1: Synthesis of compound I-7a

[0091] Under nitrogen, compound I-6a (2.0 g, 6.25 mmol, 1.0 eq), pinacol ester (2.38 g, 9.37 mmol, 1.5 eq), potassium carbonate (2.15 g, 15.6 mmol, 2.5 eq), Pd2(dba)3 (57.3 mg, 1 mmol%), and XPhos (89.4 mg, 3 mmol%) were placed in a 120 mL sealed tube with a magnetic stirrer. 25 mL of anhydrous 1,4-dioxane was added, and the mixture was reacted at 100°C for 18 h. TLC confirmed the complete reaction of the starting materials. After the reaction solution cooled to room temperature, it was filtered through celite, and the filter cake was rinsed with ethyl acetate. 50 mL of ethyl acetate and 5 mL of water were added, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 3:1 PE / EA) to give compound I-7a (605.1 mg, yield 46%). 1 H NMR (300MHz, CDCl3) δ8.42–8.29(m,2H),8.25–8.00(m,2H),7.60(s,1H),3.62( s,3H),1.70–1.55(m,1H),1.37(s,12H),1.17–1.07(m,2H),0.91–0.84(m,2H).

[0092] Step 2: Synthesis of Compound I-7

[0093] Referring to the synthesis method of compound I-1, the target compound I-7 (61.9 mg, yield 43%) was successfully obtained. 1HNMR (300MHz, CDCl3) δ8.44 (s, 1H), 8.26–8.16 (m, 2H), 7.90 (d, J = 2.4Hz, 1H), 7.79(dd,J=8.7,2.4Hz,1H),7.31(d,J=8.9Hz,1H),7.09(s,1H),7.07–6.98(m, 3H),6.60(d,J=8.7Hz,1H),3.68(s,3H),3.16(q,J=7.4Hz,2H),2.01(s,6H),1 .72–1.66(m,1H),1.33(t,J=7.4Hz,3H),1.16–1.07(m,2H),0.93–0.82(m,2H).

[0094] Example 8: Compound I-8

[0095] Synthesis route

[0096]

[0097] Referring to the synthesis method of compound I-1, the target compound I-8 (59.7 mg, yield 42%) was successfully obtained. 1 HNMR(300MHz, CDCl3)δ9.02(s,1H),8.39–8.26(m,2H),7.84-7.63(m,1H),7.38–7 .27(m,2H),7.20(dd,J=8.9,2.6Hz,1H),7.05(s,1H),7.03–6.92(m,3H),6.38(d, J=8.8Hz,1H),3.60(s,3H),3.15(q,J=7.4Hz,2H),2.41–2.11(m,1H),1.98(s,6H) ,1.83–1.66(m,1H),1.39(t,J=7.4Hz,3H),1.09–1.01(m,2H),0.86–0.74(m,2H).

[0098] Example 9: Compound I-9

[0099] Synthesis route

[0100]

[0101] Referring to the synthesis method of compound I-1, the target compound I-9 (75.8 mg, yield 51%) was successfully obtained. 1HNMR(300MHz,DMSO-d6)δ10.53(s,1H),9.94(s,1H),8.55(d,J=2.3Hz,1H),7.95(d d,J=8.8,2.4Hz,1H),7.64(d,J=2.7Hz,1H),7.50–7.40(m,2H),7.32(d,J=8.8Hz,1 H),7.16–6.96(m,3H),6.29(d,J=8.9Hz,1H),4.19–4.05(m,2H),3.58(s,3H),3.17 (d,J=3.9Hz,1H),2.01(s,3H),1.98(s,6H),1.31–1.25(m,2H),0.86–0.83(m,2H).

[0102] Example 10: Compound I-10

[0103] Synthesis route

[0104]

[0105] Step 1: Synthesis of compound I-10a

[0106] Compound I-1c (292.5 mg, 0.76 mmol, 1.0 eq), 1-methylcyclopropane-1-carboxylic acid (76.0 mg, 0.76 mmol, 1.0 eq), HATU (317.7 mg, 0.84 mmol, 1.1 eq), and DIPEA (196.1 mg, 1.52 mmol, 2.0 eq) were placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. Dissolved in 3 mL of DMF was added and stirred at room temperature for 12 h. TLC confirmed the complete reaction of the starting materials. 30 mL of ethyl acetate and 5 mL of water were added, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 40:1 CHCl / MeOH) to afford compound I-10a (167.5 mg, 66% yield). 1 H NMR (300MHz, CDCl3) δ8.43 (dd, J=8.9, 2.3Hz, 1H), 8.10 (d, J=2.3Hz, 1H), 7.84 (s, 1H), 7.76 (d ,J=8.9Hz,1H),7.28(s,1H),3.60(s,3H),1.51(s,3H),1.40-1.30(m,2H),0.78–0.66(m,2H).

[0107] Step 2: Synthesis of Compound I-10

[0108] Referring to the synthesis method of compound I-1, the target compound I-10 (62.3 mg, yield 42%) was successfully obtained. 1 HNMR(400MHz, CDCl3)δ8.38(dd,J=8.9,2.3Hz,1H),8.11(d,J=2.3Hz,1H),7.80(s,1H),7.48–7.39(m,2H),7.33(dd,J=8.7,2.4Hz,1H),7.09(s,1H) ,7.06–6.96(m,3H),6.39(d,J=8.5Hz,1H),3.67(s,3H),2.03(s,6H),1.8 4(s,1H),1.60(s,6H),1.50(s,3H),1.37–1.30(m,2H),0.75–0.65(m,2H).

[0109] Example 11: Compound I-11

[0110] Synthesis route

[0111]

[0112] Step 1: Synthesis of compound I-11a

[0113] Referring to the synthesis method of compound I-10a, the target compound I-11a (167.0 mg, yield 70%) was successfully obtained. 1 H NMR (300MHz, CDCl3) δ8.44(dd,J=8.8,2.2Hz,1H),8.24(s,1H),8.16(d,J=2.2Hz,1H),7.76(d,J=8.8Hz,1H),7.28(s,1H), 4.30–4.07(m,2H),3.58(s,3H),2.82–2.63(m,2H),2.54–2.37(m,1H),1.99–1.85(m,2H),1.84–1.71(m,2H),1.46(s,9H).

[0114] Step 2: Synthesis of Compound I-11

[0115] Compound I-11a (148.2 mg, 0.32 mmol, 1.0 eq) was placed in a 15 mL sealed tube with a magnetic stirrer. 2 mL of anhydrous tetrahydrofuran was added to dissolve the mixture and stirred at room temperature. Subsequently, 2 mL of a 2 M solution of hydrogen chloride in ethyl acetate was added, and the reaction system was stirred at room temperature for 1 h. The deprotected amine hydrochloride was obtained by removing the ethyl acetate. Under a nitrogen atmosphere, the deprotected amine hydrochloride, compound I-2h (93.9 mg, 0.25 mmol, 0.8 eq), Pd(dppf)Cl2 (4.6 mg, 2 mmol%), and potassium carbonate (132.5 mg, 0.96 mmol, 3.0 eq) were placed in a 15 mL sealed tube with a magnetic stirrer. 2 mL of 1,4-dioxane and 0.5 mL of water were added, and the mixture was reacted at 85°C for 12 h. TLC confirmed the complete reaction of the starting material. After the reaction solution cooled to room temperature, 15 mL of ethyl acetate was added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 30:1 CH2Cl2 / MeOH) to obtain the target compound I-11 (58.8 mg, 33% yield). 1 H NMR (300MHz, DMSO-d6) δ10.47(s,1H),8.61(d,J=2.4Hz,1H),7.92(dd,J=8.8,2.4Hz,1H),7.46–7.42(m,2H),7.38(dd,J=8.6,2.4Hz,1H),7.27 (d,J=8.8Hz,1H),6.97(d,J=9.1Hz,2H),6.30(d,J=8.6Hz,1H),5.02(s,1H),3.58(s,3H),2.94–2.59(m,5H),2.03–1.74(m,10H),1.43(s,6H).

[0116] Example 12: Compound I-12

[0117] Synthesis route

[0118]

[0119] Step 1: Synthesis of compound I-12a

[0120] Referring to the synthesis method of compound I-10a, the target compound I-12a (100.0 mg, yield 35%) was successfully obtained. 1HNMR (300MHz, DMSO-d6) δ10.30(s,1H),8.58(d,J=2.3Hz,1H),8.05(dd,J=8.8,2.3Hz,1H),7.83(s,1H),7.69(d,J=8.8H z,1H),4.61(d,J=4.4Hz,1H),3.66–3.53(m,1H),3.49(s,3H),2.39–2.18(m,1H),1.96–1.77(m,4H),1.23–1.08(m,4H).

[0121] Step 2: Synthesis of Compound I-12

[0122] Referring to the synthesis method of compound I-1, the target compound I-12 (66.1 mg, yield 45%) was successfully obtained. 1 HNMR (300MHz, DMSO-d6) δ10.16(s,1H),8.57(d,J=2.3Hz,1H),7.91(dd,J=8.8,2.3Hz,1H),7.44(d ,J=2.4Hz,1H),7.43(s,1H),7.37(dd,J=8.6,2.4Hz,1H),7.28(d,J=8.8Hz,1H),7.13–7.07(m,2H), 7.07–7.00(m,1H),6.26(d,J=8.6Hz,1H),5.00(s,1H),4.60(d,J=4.4Hz,1H),3.58(s,3H),3.43–3. 38(m,1H),2.34–2.18(m,1H),1.97(s,6H),1.9–1.77(m,4H),1.58–1.36(m,8H),1.28–1.08(m,2H).

[0123] Example 13: Compound I-13

[0124]

[0125] Referring to the synthesis method of compound I-1, the target compound I-13 (55.1 mg, yield 38%) was successfully obtained. 1HNMR(300MHz,DMSO-d6)δ10.15(s,1H),8.57(d,J=2.3Hz,1H),7.90(dd,J=8.8,2.3 Hz,1H),7.46–7.41(m,2H),7.38(dd,J=8.6,2.3Hz,1H),7.26(d,J=8.8Hz,1H),6.96 (d,J=9.1Hz,2H),6.30(d,J=8.5Hz,1H),5.00(s,1H),4.60(d,J=4.4Hz,1H),3.58(s ,3H),2.34–2.18(m,2H),2.05–1.73(m,10H),1.56-1.37(m,8H),1.26–1.12(m,2H).

[0126] Example 14: Compound I-14

[0127]

[0128] Step 1: Synthesis of compound I-14a

[0129] Under nitrogen, compound I-1c (450.0 mg, 1.78 mmol, 1.0 eq) and NEt3 (359.6 mg, 3.56 mmol, 2.0 eq) were placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 5 mL of anhydrous dichloromethane was added to dissolve the mixture, and the mixture was stirred at 0°C for 5 min. Solid triphosgene (158.4 mg, 0.53 mmol, 0.3 eq) was added all at once, and the reaction system was stirred at 0°C for 1 h. TLC confirmed the complete reaction of the starting material. Morpholine (309.7 mg, 3.56 mmol, 2.0 eq) was added to the reaction system, and the reaction system was transferred to room temperature and stirred for 2 h. TLC confirmed the complete reaction of the starting material. Saturated ammonium chloride solution was added dropwise under an ice bath to quench the reaction. 15 mL of dichloromethane was added, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the product was purified by column chromatography (200-300 mesh silica gel, 40:1 CH 2 Cl 2 / MeOH) to give compound I-14a (554.0 mg, yield 85%). 1 HNMR(300MHz, CDCl3)δ8.24(dd,J=8.9,2.4Hz,1H),7.99(d,J=2.4Hz,1H),7.75( d,J=8.9Hz,1H),6.92(s,1H),3.80–3.73(m,4H),3.59(s,3H),3.57–3.51(m,4H).

[0130] Step 2: Synthesis of Compound I-14

[0131] Referring to the synthesis method of compound I-1, the target compound I-14 (25.9 mg, yield 46%) was successfully obtained. 1 HNMR (300 MHz, CDCl3) δ8.17 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.41–7.31 (m, 2H), 7.10–6.97 (m, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 8.5 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 3.66 (s, 3H), 3.53 (d, J = 5.0 Hz, 4H), 2.02 (s, 6H), 1.89 (s, 1H), 1.60 (s, 6H). Example 15: In vitro activity assay for BRD4 (BD1 and BD2) protein levels

[0132] The BRD4 (BD2) protein activity inhibition experiment of the compounds in the above examples was tested, and the specific operation was as follows:

[0133] 1. Experimental methods:

[0134] Binding reaction process

[0135] (1) Prepare 1× Assay buffer.

[0136] (2) Preparation of compound concentration gradient: The test compound was diluted 3-fold to a final concentration of 60 μM (BD1) or 3 μM (BD2), with each concentration tested in a single well. The solution was diluted to a 1000-fold final concentration in a 384-well Source plate, and then 20 nL was transferred to a 384-well reaction plate using an Echo550. 20 nL of 100% DMSO was transferred to the Max well, and 20 nL of the highest concentration of the positive compound was transferred to the Min well.

[0137] (3) Prepare 4× protein solution using 1× reaction solution.

[0138] (4) Add 5 μL of 4× protein solution to each well, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 15 minutes.

[0139] (5) Prepare 4× polypeptide solution using 1× reaction solution.

[0140] (6) Add 5 μL of 4× peptide solution to each well of the reaction plate and centrifuge at 1000 rpm for 1 minute.

[0141] (7) Add 10 μL of detection solution, centrifuge at 1000 rpm for 60 seconds, gently shake to mix, and incubate at room temperature for 60 minutes.

[0142] (8) Read the data using EnVision.

[0143] 2. Data processing:

[0144] %Inhibition = (Signal_max - Signal_sample) / (Signal_max - Signal_min) x 100. Fitting the dose-effect curve: With the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log (inhibitor) vs. response-Variable slope analysis software GraphPadPrism5 was used to fit the dose-effect curve to obtain the IC value of the compound for protein binding inhibition. 50 value.

[0145] 3. Experimental Results

[0146] The results of the protein activity test of the compounds of the present invention are as follows:

[0147] Table 1. BET protein activity test results of the compounds

[0148]

[0149] As shown in Table 1 above, the compounds of the present invention exhibit high selectivity for BRD4 BD2. Compared to the positive control compound ABBV-744, some of the compounds of the present invention exhibit superior selectivity for BRD4 BD2. It is important to note that all tests performed in this invention were performed at the nanomolar level. Even though some compounds were less selective than ABBV-744, their novelty still demonstrates selectivity for BRD4 BD2.

[0150] Example 16: Cell Anti-Proliferation Experiment (MV-411, THP-1)

[0151] 1. Experimental Procedure

[0152] (1) Cell plating: Leukemia cells (MV-411 and THP-1) in the logarithmic growth phase were prepared into a cell suspension at a concentration of 1×10 cells per well. 3 The cells were added to a 96-well cell culture plate at a density of 50 μL.

[0153] (2) Drug treatment: The test compound was tested at a final concentration of 20 μM, starting with 4-fold dilutions, with 8 concentrations, and 3 replicates per concentration. 50 μL of the test compound was added to the culture wells and the culture was continued for 120 h.

[0154] (3) After 120 h of cell culture, the culture plate was removed and allowed to stand at room temperature for 10 minutes. 100 μL of CellTiter-Lumi solution was added and shaken on a microplate for 2 minutes. After standing at room temperature for 10 minutes, the chemiluminescence value was detected using a microplate reader.

[0155] 2. Data Processing

[0156] %Inhibition = [(Signal_sample - Signal_min) / (Signal_max - Signal_min] × 100% Fitting of the dose-effect curve: With the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log (inhibitor) vs. response-Variable slope analysis software GraphPadPrism 5 was used to fit the dose-effect curve to obtain the IC of the compound for inhibiting cell proliferation. 50 Signal_sample: Chemiluminescence value of the experimental well (containing cells, culture medium, CellTiter-Lumi solution, and drug solution); Signal_max: Chemiluminescence value of the control well (containing cells, culture medium, CellTiter-Lumi solution, but no drug); Signal_min: Chemiluminescence value of the blank well (containing culture medium and CellTiter-Lumi solution, but no cells or drug).

[0157] 3. Experimental Results

[0158] The results of the cell anti-proliferation experiment of the compounds of the present invention are as follows:

[0159] Table 2. Cell anti-proliferation test results of some compounds

[0160] Compound number MV-411 (μM) THP-1 (μM) I-5 1.03 4.04 I-6 0.40 2.79 I-7 2.10 3.54 I-8 0.20 0.53 I-10 0.29 1.93 I-12 0.55 3.40 I-13 0.69 2.32

[0161] As shown in the above data, the compounds of the present invention have good inhibitory effects on MV-411 and THP-1.

[0162] Example 17: Cytotoxicity to Normal Cells (NIH / 3T3)

[0163] 1. Experimental Procedure

[0164] (1) Cell plating: Mouse embryonic fibroblasts (NIH / 3T3) in the logarithmic growth phase were prepared into a cell suspension at a concentration of 1×10 cells per well. 3 The cells were added to a 96-well cell culture plate at a density of 50 μL.

[0165] (2) Drug treatment: The test compound was tested at a final concentration of 30 μM, starting with 3-fold dilutions, with 8 concentrations, and 3 replicates per concentration. 50 μL of the test compound was added to the culture wells and the cells were cultured for 120 h.

[0166] (3) After 120 h of cell culture, the culture plate was removed and allowed to stand at room temperature for 10 minutes. 100 μL of CellTiter-Lumi solution was added and shaken on a microplate for 2 minutes. After standing at room temperature for 10 minutes, the chemiluminescence value was detected using a microplate reader.

[0167] 2. Data Processing

[0168] %Inhibition = [(Signal_sample - Signal_min) / (Signal_max - Signal_min] × 100% Fitting of the dose-effect curve: With the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log (inhibitor) vs. response-Variable slope analysis software GraphPadPrism 5 was used to fit the dose-effect curve to obtain the IC of the compound for inhibiting cell proliferation. 50 Signal_sample: Chemiluminescence value of the experimental well (containing cells, culture medium, CellTiter-Lumi solution, and drug solution); Signal_max: Chemiluminescence value of the control well (containing cells, culture medium, CellTiter-Lumi solution, but no drug); Signal_min: Chemiluminescence value of the blank well (containing culture medium and CellTiter-Lumi solution, but no cells or drug).

[0169] 3. Experimental Results

[0170] The results of the cell anti-proliferation experiment of the compounds of the present invention are as follows:

[0171] Table 3. Effects of some compounds on normal cells

[0172] Compound number NIH / 3T3 (μM) I-8 >30 I-10 >30

[0173] As shown in Table 3, the IC values ​​of some of the compounds of the present invention with significant anti-leukemia activity against normal healthy cells (NIH / 3T3) are 50 The value exceeded 30 μM, showing an extremely high selectivity index, indicating that it has low toxicity to normal cells while effectively killing cancer cells, and has a high therapeutic safety window.

Claims

1. An arylpyridone compound as shown in Formula I or a pharmaceutically acceptable salt thereof, whose structure is as follows: in, R 1 is H or halogen; R 2 independently selected from hydrogen, C1-C3 alkyl, CH2-R 4 、COR 4 ; X is N or CH; R 3 Selected from R 4 Independently selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl group is optionally replaced by one or more R a Substituted, where R a Independently selected from methyl and hydroxy.

2. The arylpyridone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is any of the following compounds:

3. The arylpyridone compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is an acid addition salt formed by the compound of any one of claims 1 or 2 and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, fumaric acid, p-toluenesulfonic acid or ferulic acid.

4. The method for preparing arylpyridones according to claim 1 or 2, wherein: The synthetic route of the compound is as follows: in: R 1 is H or halogen; R 2 independently selected from hydrogen, C1-C3 alkyl, CH2-R 4 、COR 4 ; X is N or CH; R 3 Selected from R 4 Independently selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl group is optionally replaced by one or more R a Substituted, where R a Independently selected from methyl and hydroxy; The specific synthesis steps are as follows: (1) Compound II-1 and II-2 are reacted by Suzuki reaction to obtain compound I; or (2) Compound II-3 and II-4 are reacted by Suzuki reaction to obtain compound I.

5. The method according to claim 4, characterized in that: Under nitrogen protection, II-1 (1 eq), II-2 (1.2 eq), Pd (dppf) Cl2 (2 mol%) and 2.0 eq potassium carbonate were placed in a sealed tube with a magnetic stirrer, 1,4-dioxane and water were added in a ratio of 5:1, and the mixture was reacted at 85 ° C for 12 h to obtain product I. Alternatively, under nitrogen protection, II-3 (1.2 eq), II-4 (1 eq), Pd (dppf) Cl2 (2 mol%) and 2.0 eq potassium carbonate were placed in a sealed tube with a magnetic stirrer, 1,4-dioxane and water were added in a ratio of 5:1, and the mixture was reacted at 85 ° C for 12 h to obtain product I.

6. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or 2 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

7. Use of the arylpyridone compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 and the pharmaceutical composition according to claim 6 in the preparation of a BD2 selective BET inhibitor.

8. Use of the arylpyridone compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 and the pharmaceutical composition according to claim 6 in the preparation of a drug for treating cancer.

9. Use of the arylpyridone compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 and the pharmaceutical composition according to claim 6 in the preparation of a drug for treating leukemia.

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