Aryl-substituted five-membered nitrogen heterocyclic amide derivatives and uses thereof

Abstract

The present invention discloses a class of aromatic substituted five-membered nitrogen heterocyclic amide derivatives and uses thereof, belonging to the technical field of pharmaceutical chemistry. The present invention studies the pharmacological activity of YTHDC1-specific inhibitors, and provides aromatic substituted five-membered nitrogen heterocyclic amide derivatives shown in formula I, which have high inhibitory activity against YTHDC1; in vitro experiments have shown that they can effectively inhibit the proliferation of acute myeloid leukemia cells, significantly block the acute myeloid leukemia cell cycle at the G0 / G1 phase, and induce the differentiation and apoptosis of acute myeloid leukemia cells; the aromatic substituted five-membered nitrogen heterocyclic amide derivatives and their salts or pharmaceutical compositions provided by the present invention provide a new option for the development of anti-tumor drugs targeting YTHDC1.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of aromatic substituted five-membered nitrogen heterocyclic amide derivatives and uses thereof. Background Art

[0002] N6-methyladenosine 6 A) modification is the most common epigenetic modification in eukaryotic mRNA. 6 A participates in and affects all stages of RNA metabolic processing, including alternative splicing, folding, translation, and decay. 6 A modification is a dynamic and reversible process. The three most important regulatory factors are methyltransferase, demethylase and m 6 A reads protein. First, m 6 A methylation is mainly mediated by the methyltransferase complex (MTC), the core components of which include WT1-associated protein (WTAP) and methyltransferase-like protein 3 / 14 (METTL3) / (METTL14). Methylated RNA can be demethylated by the demethylases alkylation repair protein B (AlkB) homolog 5 (ALKBH5) and FTO. In addition, methylated RNA can be demethylated by YTH m 6 A RNA binding protein F2 (YTHDF2), YTHDF1, YTH m 6 A RNA binding protein C1 (YTHDC1) and other recognition. So far, except for METTL3 and FTO, the rest of the m 6 The biological functions and mechanisms of action of dynamically modified regulatory factors have not yet been elucidated, and there is a lack of reports on highly active and highly selective small molecule inhibitors.

[0003] YTHDC1 (also known as YT521-B) is currently found to be the only member of the YTH family that is localized in the nucleus rather than the cytoplasm. It was first discovered in 1998 that it can interact with the RNA binding protein RA301, and also interacts with the splicing factors SC35 and SF2, thus being identified as a splicing-related protein. The YTH domain in YTHDC1 specifically recognizes m 6A modification, and preferentially recognizes the G(m6A)C motif through the hydrophobic aromatic cage pocket formed by its W377, W428, L430 and L439. The latest research results show that YTHDC1 is closely related to the occurrence and development of many diseases such as acute myeloid leukemia, liver cancer, pancreatic cancer, breast cancer, lung cancer, bladder cancer, glioma and hepatitis B, and its specific regulatory mechanisms have been revealed in the development of many diseases. As a potential important therapeutic target for the above diseases, YTHDC1 has begun to attract great attention from major pharmaceutical companies and drug research and development institutions in recent years. However, to date, there is only one report on small molecule regulators targeting YTHDC1.

[0004] Therefore, the development of highly active and specific YTHDC1 small molecule inhibitors will not only provide new means for the clinical treatment of malignant tumors and various related diseases such as hepatitis B, but will also be conducive to exploring the mechanism of action of YTHDC1, that is, the study of its feedback promotion mechanism in physiological and pathological processes. Summary of the invention

[0005] The present invention synthesizes a class of aromatic substituted five-membered nitrogen heterocyclic amide derivatives, which have high inhibitory activity against YTHDC1 and provide a new means for treating various YTHDC1-related diseases such as tumors (such as leukemia) and hepatitis B.

[0006] The present invention first provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein the structure of formula I is as follows:

[0007] ;

[0008] in,

[0009] X1 is NH, X2 is CH, and X3 is CH; or, X1 is CH, X2 is NH, and X3 is CH; or, X1 is NH, X2 is N, and X3 is CH; or, X1 is NH, X2 is CH, and X3 is N (as known in the art, is a five-membered conjugated heteroaromatic ring structure, and a corresponding five-membered heteroaromatic ring is formed according to the types of X1, X2, and X3);

[0010] ;

[0011] R 1a is selected from substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 2~6 alkyl;

[0012] R 1a wherein the substituent of the substituted 3-6 membered cycloalkyl is selected from halogen, amino, N,N-dimethylamino, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, ;

[0013] R 1a wherein the substituted C 2~6 The substituents of the alkyl group are selected from halogen, amino, N,N-dimethylamino, cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, methoxy, ethoxy, ;

[0014] R 1b Selected from substituted or unsubstituted ;

[0015] n1 is selected from 1, 2 or 3;

[0016] R 1b In the above, the substituted The substituents are selected from halogen, amino, N,N-dimethylamino, cyano, hydroxy, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, ;

[0017] R 1c Selected from C 1~4 Alkyl, 3~6 membered cycloalkyl, allyl, , methoxycarbonyl, ethoxycarbonyl, or methoxy-substituted C 1~4 alkyl;

[0018] R 1d Selected from , substituted or unsubstituted 3-6 membered cycloalkyl;

[0019] R 1d wherein the substituent of the substituted 3-6 membered cycloalkyl is selected from halogen, amino, N,N-dimethylamino, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, ;

[0020] R 1e Selected from , substituted or unsubstituted 3-6 membered cycloalkyl;

[0021] R 1e wherein the substituent of the substituted 3-6 membered cycloalkyl is selected from halogen, amino, N,N-dimethylamino, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, ;

[0022] R2 is selected from hydrogen, -N(R 2a )2. Halogen substituted or unsubstituted ;

[0023] R 2a Selected from C 1~4 Alkyl, C1~4 Haloalkyl or C 1~4 Deuterated alkyl;

[0024] n2 is selected from 0, 1, 2 or 3;

[0025] R3 is selected from hydrogen, halogen or C 1~4 Alkoxy;

[0026] R4 is selected from hydrogen, substituted or unsubstituted C 1~4 Alkoxy;

[0027] In R4, the substituted C 1~4 The substituent of the alkoxy group is selected from deuterium or N,N-dimethylamino.

[0028] In some embodiments of the present invention, R1 is selected from the following groups:

[0029]

[0030] In some embodiments of the present invention, R2 is selected from hydrogen, -N(R 2a )2. Fluorine substituted or unsubstituted ; R 2a Selected from C 1~2 Alkyl, C 1~2 Fluorinated alkyl or C 1~2 deuterated alkyl; n2 is selected from 1, 2 or 3.

[0031] In some preferred embodiments of the present invention, R2 is selected from hydrogen, .

[0032] In some embodiments of the present invention, R3 is selected from hydrogen, fluorine, chlorine, bromine or methoxy.

[0033] In some embodiments of the present invention, R4 is selected from hydrogen, methoxy, deuterated methoxy, ethoxy, deuterated ethoxy, .

[0034] The present invention also provides some specific compounds, which are selected from:

[0035]

[0036]

[0037]

[0038]

[0039] In a second aspect, the present invention further provides a pharmaceutical composition, which comprises the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and is supplemented with pharmaceutically acceptable auxiliary ingredients.

[0040] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining any compound of Formula I or a pharmaceutically acceptable salt thereof, or a mixture thereof, with one or more pharmaceutically acceptable auxiliary ingredients.

[0041] In a third aspect, the present invention provides use of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the preparation of a YTHDC1 small molecule inhibitor.

[0042] In a fourth aspect, the present invention provides use of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing and / or treating leukemia.

[0043] Preferably, in the above use, the leukemia is acute myeloid leukemia.

[0044] Beneficial effects of the present invention:

[0045] The present invention synthesizes a class of aromatic-substituted five-membered nitrogen heterocyclic amide derivatives, which have high inhibitory activity against YTHDC1, and provide a new means for the treatment of various YTHDC1-related diseases such as tumors (such as leukemia) and hepatitis B. In vitro experiments have shown that this class of compounds can effectively inhibit the proliferation of acute myeloid leukemia cells in vitro, significantly block the acute myeloid leukemia cell cycle at the G0 / G1 phase, and induce the differentiation and apoptosis of acute myeloid leukemia cells, providing a new option for the development of anti-tumor drugs targeting YTHDC1. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The graph shows the results of in vitro cell experiments of compounds 66, 69, 71 of the present invention and the positive control YL-5092. DETAILED DESCRIPTION

[0047] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0048] Example 1

[0049]

[0050] The preparation conditions of Example 1 include: I, chloromethyl trimethylsilyl ethyl ether, potassium tert-butoxide, N,N-dimethylformamide, 0°C to 70°C, overnight; II, sodium hydroxide, ethanol: water, 60°C, 1.5 hours; III, p-toluenesulfonylmethyl isocyanide, potassium carbonate, reflux, 4 hours; IV, palladium carbon / hydrogen, room temperature, 4 hours; V, 1-butyl phosphoric anhydride (T4P), N,N-dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h; VI, (2-(methoxycarbonyl)phenyl)boric acid, tetrakis(triphenylphosphine)palladium, potassium carbonate, dioxane: water (5:1), 90°C, 16h; VII, trifluoroacetic acid, tetrahydrofuran, room temperature, overnight; VIII, 4-aminotetrahydropyran, 1-butyl phosphoric anhydride (T4P), N,N-dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h.

[0051] Intermediate A-1: ​​4-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of ethyl pyrrole-2-carboxylate.

[0052] Potassium tert-butoxide (10.10 g, 90 mmol) was added to 4-bromo-1 H -pyrrole-2-carboxylic acid methyl ester (6.54 g, 30 mmol) in DMF solution (20 mL), followed by dropwise addition of chloromethyl trimethylsilyl ethyl ether (SEMCl) (10.64 ml, 60 mmol). The reaction solution was then stirred at 70 ° C overnight. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (3 × 100 mL), washed with saturated NaHCO3 solution (2 × 100 mL), washed with saturated sodium chloride solution (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (PE: EA = 0 → 5%) to obtain colorless oily solid A-1. 1 H NMR (400MHz, DMSO- d 6) δ7.49 (d, J =2.1Hz, 1H), 6.93 (d, J =2.3Hz, 1H), 5.56 (s, 2H), 3.72 (s, 3H), 3.46 (t, d, J =7.8Hz, 2H), 0.78 (t, J =8.1 Hz, 2H), 0.06 (s, 9H). MS(ESI) m / z :215.12 [M – OCH2CH2Si(CH3)3] - .

[0053] Intermediate A-2: 4-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of pyrrole-2-carboxylic acid.

[0054] Add 2N NaOH aqueous solution (10.0 mL, 20.0 mmol) to an ethanol solution (5.0 mL) of intermediate A-1 (3.5 g, 1.0 mmol). Stir at 60 °C for 1.5 h and evaporate under reduced pressure. Dilute the residue with water and acidify with hydrochloric acid (3N) aqueous solution to pH 3-4. Filter, wash the filter cake with a small amount of water, dry it and use it in the next step without further purification.

[0055] Intermediate B-1: Preparation of 5-(4-nitrophenyl)oxazole.

[0056] Dissolve p-nitrobenzaldehyde (3.78 g, 25.0 mmol) in anhydrous ethanol, then add p-toluenesulfonylmethyl isocyanide (4.78 g, 30.0 mol) and anhydrous potassium carbonate (6.91, 50.0 mmol). Reflux the reaction system for 4 hours. After TLC detection, the p-nitrobenzaldehyde reaction is complete, and the reaction system is poured into water and stirred thoroughly. The above solution is filtered and the filter cake is dried. The filter cake is recrystallized with ethyl acetate and n-hexane to obtain a white solid B-1. 1 H NMR (400 MHz, DMSO- d 6) 8.59 (1H, s), 8.27–8.37 (2H, m), 7.94–8.05 (3H, m). MS(ESI) m / z : 190.87 [M + H] + .

[0057] Intermediate B-2: Preparation of 4-(1,3-oxazol-5-yl)aniline.

[0058] After adding methanol to dissolve the intermediate B-1 (1.0 g, 5.24 mmol), 10% palladium on carbon (0.1 eq) was added. Subsequently, the mixture was replaced with a hydrogen balloon three times and stirred at room temperature for 4 hours under a hydrogen balloon. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the intermediate B-2. It can be used in the next step without further purification. MS (ESI) m / z : 161.04 [M + H] + .

[0059] Intermediate A-3: 4-bromo-N-(4-(oxazol-5-yl)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -Preparation of pyrrole-2-carboxamide.

[0060] To an ultra-dry tetrahydrofuran solution (10 mL) containing intermediate A-2 (1.08 g, 3.40 mmol), B-2 (0.54 g, 3.40 mmol) and 4-dimethylaminopyridine (DMAP) (0.82 mg, 6.80 mmol) was added 1-butylphosphonic anhydride (T4P, 50 wt.% ethyl acetate solution, 6.10 mL, 8.50 mmol) and stirred at room temperature for 0.5 hours. After quenching with methanol, the solvent was removed under reduced pressure. The residue was loaded on silica gel and purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:1) to obtain a yellow solid A-3. 1 H NMR (400 MHz, DMSO- d 6) δ 10.24 (s, 1H), 8.50 (s, 1H), 7.91(d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.21 (d, J = 4.0Hz, 1H), 6.51 (d, J = 4.0 Hz, 1H), 5.89 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.93 – 0.84 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z: 345.24 [M – OCH2CH2Si(CH3)3] - .

[0061] Intermediate A-4: 2-(5-(4-(oxazole-5-phenyl)carbamoyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1 H Preparation of methyl 1-pyrrol-3-yl)benzoate.

[0062] Add intermediate A-3 (1.07 g, 2.31 mmol), (2-(methoxycarbonyl)phenyl)boric acid (0.58 g, 3.23 mmol), potassium carbonate (0.96 g, 6.93 eq) and tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol) into a flask, and then add a mixed solvent (24 mL) of dioxane: water (volume ratio 5:1). The system was replaced with argon three times, and then heated to 90 °C for 16 hours while maintaining argon protection. TLC detected that the reaction of intermediate A3 was complete. The reaction system was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a yellow solid. MS (ESI) m / z: 345.48 [M – OCH2CH2Si(CH3)3]- .

[0063] Intermediate A-5: 2-(5-(4-(oxazole-5-phenyl)carbamoyl)-1 H -pyrrol-3-yl)benzoic acid.

[0064] Trifluoroacetic acid (0.36 mL, 4.68 mmol) was added to a tetrahydrofuran solution (15 mL) of intermediate A-4 (0.81 g, 1.56 mmol) at room temperature and stirred overnight at room temperature. After TLC detection, the reaction system was concentrated under reduced pressure to remove the solvent and excess trifluoroacetic acid. The residue was dissolved in an appropriate amount of methanol, and 2N NaOH aqueous solution (10.0 mL, 20.0 mmol) was added, stirred at 60 ° C for 1.5 h, and evaporated under reduced pressure. The residue was diluted with water and acidified to pH 3~4 with hydrochloric acid (3N) aqueous solution. Filter, wash the filter cake with a small amount of water, dry it and use it in the next step without further purification. MS (ESI) m / z : 373.99[M + H] + .

[0065] Compound 2: N-(4-(oxazol-5-yl)phenyl)-4-(2-(tetrahydro-2 H -pyran-4-yl)carbamoyl)phenyl)-1 H -Preparation of pyrrole-2-carboxamide.

[0066] To an ultra-dry tetrahydrofuran solution (10 mL) containing intermediate A-5 (80 mg, 0.21 mmol), 4-aminotetrahydropyran (38 μL, 0.32 mmol) and 4-dimethylaminopyridine (DMAP) (51 mg, 0.42 mmol) was added 1-butylphosphonic anhydride (T4P, 50 wt. % ethyl acetate solution, 0.38 mL, 0.53 mmol) and stirred at room temperature for 0.5 hours. After quenching with methanol, the solvent was removed under reduced pressure. The residue was loaded on silica gel and purified by silica gel chromatography (dichloromethane / ethyl acetate = 4:1) to obtain compound 2. 1 H NMR (400 MHz, DMSO- d 6) δ 11.85 (s, 1H), 10.08 (s, 1H), 8.41 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.96 – 7.81 (m, 2H), 7.79 – 7.67 (m, 2H),7.60 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.43 (ddd,J = 8.0, 5.9, 2.9 Hz, 1H),7.35 (t, J = 2.1 Hz, 1H), 7.30 – 7.24 (m, 2H), 7.19 (dd, J = 3.0, 1.6 Hz,1H), 3.94 (ddt, J = 15.1, 10.9, 5.5 Hz, 1H), 3.78 (dt, J = 11.6, 3.6 Hz, 2H),3.33 (d, J = 5.0 Hz, 2H), 1.71 (dd, J = 12.8, 4.0 Hz, 2H), 1.48 – 1.35 (m,2H). HRMS (m / z): calculated for C 26 H 24 N4O4 + [M+H] + 457.1768; found, 457.1759.

[0067] Example 2

[0068]

[0069] The preparation conditions of Example 2 include: I, chloromethyl trimethylsilyl ethyl ether, potassium tert-butoxide, N,N-dimethylformamide, 0°C to 70°C, overnight; II, sodium hydroxide, ethanol: water, 60°C, 1.5 hours; III, 1-butylphosphoric anhydride (T4P), N , N -dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h; IV, (2-(methoxycarbonyl)phenyl)boric acid, tetrakis(triphenylphosphine)palladium, potassium carbonate, dioxane: water (5:1), 90℃, 16h; V, trifluoroacetic acid, tetrahydrofuran, room temperature, overnight; VI, azetidine, 1-butylphosphoric anhydride (T4P), N , N -Dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h.

[0070] Intermediate A-6: 5-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of ethyl pyrrole-2-carboxylate.

[0071] Use 5-bromo-1 H -pyrrole-2-carboxylic acid ethyl ester was used as the starting material, and the preparation method was referred to A-1 in Example 1.1 HNMR (400 MHz, DMSO- d 6) δ 12.90 (s,1H), 7.59 (d, J =8.3Hz, 1H) 7.52 (s, 1H),7.50 (dd, J =6.3, 8.3 Hz, 1H), 7.39-7.43 (m, 1H), 7.00 (s,1H), 4.21 (q, J =6.9 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). MS (ESI) m / z : 229.38 [M – OCH2CH2Si(CH3)3] - .

[0072] Intermediate A-7: 5-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of pyrrole-2-carboxylic acid.

[0073] The preparation method is similar to that of A-2 in Example 1.

[0074] Intermediate A-8: 5-bromo- N Preparation of -(4-(oxazol-5-yl)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxamide.

[0075] The preparation method is similar to that of A-3 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 10.24 (s, 1H), 8.50 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.69 (s,1H), 7.21 (d, J = 4.0 Hz, 1H), 6.51 (d, J = 4.0 Hz, 1H), 5.89 (s, 2H), 3.60(t, J = 8.0 Hz, 2H), 0.93 – 0.84 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z: 345.28[M – OCH2CH2Si(CH3)3] - .

[0076] Intermediate A-9: 2-(5-(4-oxazol-5-phenyl)carbamoyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1 H Preparation of methyl 2-pyrrol-2-yl)benzoate.

[0077] The preparation method is similar to that of A-4 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H),8.55 (s, 1H), 8.07 – 7.93 (m, 3H), 7.90 – 7.79 (m, 3H), 7.77 – 7.71 (m, 2H),7.63 (dd, J = 7.6, 1.4 Hz, 1H), 7.26 (d, J = 3.9 Hz, 1H), 6.27 (d, J = 3.9Hz, 1H), 5.66 (s, 2H), 3.80 (s, 3H), 3.45 – 3.30 (m, 2H), 0.86 – 0.73 (m,2H), 0.00 (s, 9H). MS (ESI) m / z: 400.33 [M – OCH2CH2Si(CH3)3] - .

[0078] Intermediate A-10: 2-(5-(4-(2-oxazol-5-yl)phenyl)carbamoyl)-1 H -pyrrol-2-yl)benzoic acid.

[0079] The preparation method is similar to A-5 in Example 1. MS (ESI) m / z: 374.1 [M + H] + .

[0080] Compound 41: N -(4-(oxazol-5-yl)phenyl)-5-(2-(azetidine-1-carbonyl)phenyl)-1 H -Preparation of pyrrole-2-carboxamide.

[0081] To an ultra-dry tetrahydrofuran solution (10 mL) containing intermediate A-5 (80 mg, 0.21 mmol), azetidine (22 μL, 0.32 mmol) and 4-dimethylaminopyridine (DMAP) (51 mg, 0.42 mmol) was added 1-butylphosphonic anhydride (T4P, 50 wt. % ethyl acetate solution, 0.38 mL, 0.53 mmol) and stirred at room temperature for 0.5 hours. After quenching with methanol, the solvent was removed under reduced pressure. The residue was loaded on silica gel and purified by silica gel chromatography (dichloromethane / ethyl acetate = 4:1) to obtain compound 41. 1 H NMR (400 MHz, DMSO- d 6) δ 11.90 (d, J = 2.7 Hz, 1H), 10.10 (s,1H), 8.48 (s, 1H), 8.00 – 7.91 (m, 2H), 7.83 (d, J = 7.9 Hz, 1H), 7.81 – 7.73(m, 2H), 7.67 (s, 1H), 7.55 (tt, J = 8.1, 3.8 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.24 (dd, J = 3.9, 2.4 Hz, 1H), 6.51 (dd, J = 3.9, 2.5 Hz, 1H), 4.05 (t, J =7.7 Hz, 2H), 3.72 (t, J = 7.6 Hz, 2H), 2.17 (p, J = 7.5 Hz, 2H). HRMS (m / z):calculated for C 24 H 20 N4O3 + [M+H] + 413.4490; found, 413.4483.

[0082] Example 3

[0083]

[0084] The preparation conditions of Example 3 include: I, 2-BOC-aminophenylboronic acid pinacol ester, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex, cesium carbonate, tricyclohexylphosphine, dioxane: water (10:1), 100°C, 8h; II, trifluoroacetic acid, tetrahydrofuran, room temperature, overnight; III, 3-(cyclopropanecarboxamido)bicyclo[1.1.1]pentane-1-carboxylic acid, 1-butylphosphonic anhydride (T4P), N,N-dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h.

[0085] Intermediate A-11: tert-butyl(2-(5-(4-(oxazol-5-yl)phenyl)carbamate)-1-(2-(3-(trimethylsilyl)ethoxy)methyl)-1 H Preparation of 2-pyrrol-2-yl)phenyl)carbamate.

[0086] Add intermediate A-8 (1.51 g, 3.25 mmol), 2-BOC-aminophenylboronic acid pinacol ester (1.45 g, 4.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.13 g, 0.16 mmol), cesium carbonate (2.12 g, 6.50 mmol), tricyclohexylphosphine (0.06 g, 0.07 mmol), and then add dioxane: water (volume ratio 10:1) mixed solvent (22 mL). The system was replaced with argon three times, and then heated to 100 ° C for 8 hours while maintaining argon protection. After the reaction of intermediate A-8 was completed, TLC was detected. The reaction system was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.29 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 8.02 – 7.97 (m, 2H), 7.83 (dd, J = 8.9, 2.2 Hz, 3H),7.73 (s, 1H), 7.56 (ddd, J = 8.5, 7.4, 1.7 Hz, 1H), 7.45 (dd, J = 7.7, 1.7Hz, 1H), 7.38 – 7.24 (m, 2H), 6.38 (d, J= 3.9 Hz, 1H), 5.62 (s, 2H), 3.45 –3.37 (m, 2H), 1.52 (s, 9H), 0.92 – 0.59 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z:457.36 [M – OCH2CH2Si(CH3)3-Boc] - .

[0087] Intermediate A-12: 5-(2-aminophenyl)-N-(4-(oxazol-5-yl)phenyl)-1 H -Preparation of pyrrole-2-carboxamide.

[0088] Trifluoroacetic acid (0.36 mL, 4.68 mmol) was added to a tetrahydrofuran solution (15 mL) of intermediate A-11 (0.81 g, 1.56 mmol) at room temperature, and stirred overnight at room temperature. After TLC detection, the reaction system was concentrated under reduced pressure to remove the solvent and excess trifluoroacetic acid. The residue was dissolved in an appropriate amount of methanol, and a small amount of triethylamine was added to adjust the pH of the solution to near neutrality, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a gray solid. MS (ESI) m / z : 345.29 [M + H] + .

[0089] Compound 72: 5-(2-(3-(cyclopropanecarbonyl)bicyclo[1.1.1]pentane-1-carboxamido)phenyl)- N -(4-(oxazol-5-yl)phenyl)-1 H -Preparation of pyrrole-2-carboxamide.

[0090] The preparation method is similar to that of Compound 2 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 11.83 (s,1H), 10.14 (s, 1H), 9.24 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 7.95 – 7.88 (m,2H), 7.75 – 7.68 (m, 2H), 7.67 – 7.55 (m, 2H), 7.47 (dd, J = 7.4, 1.9 Hz,1H), 7.30 (pd, J = 7.3, 1.8 Hz, 2H), 7.16 (d, J = 3.8 Hz, 1H), 6.42 (d,J =3.8 Hz, 1H), 2.24 (s, 6H), 1.45 (td, J = 7.6, 3.8 Hz, 1H), 0.63 (tt, J = 7.8,2.9 Hz, 4H). HRMS (m / z): calculated for C 30 H 27 N5O4 + [M+H] + 522.2063; found,522.2056.

[0091] Example 4

[0092]

[0093] The preparation conditions of Example 4 include: I, 1-bromo-2-(3-methoxypropoxy)benzene, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex, cesium carbonate, dioxane: water (10:1), 100°C, 8h; II, trifluoroacetic acid, tetrahydrofuran, room temperature, overnight; III, 1-butylphosphonic anhydride (T4P), N,N-dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h.

[0094] Intermediate A-13: 5-(2-(3-methoxypropoxy)phenyl)-1 H - Preparation of methyl pyrrole-2-carboxylate.

[0095] Commercially available 5-(methoxycarbonyl)pyrrole-2-boronic acid (200 mg, 0.80 mmol), 1-bromo-2-(3-methoxypropoxy)benzene (220 mg, 0.90 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (65 mg, 0.08 mmol), cesium carbonate (782 mg, 2.40 mmol), and then a mixed solvent (22 mL) of dioxane: water (volume ratio 10:1) were added to the flask. The system was replaced with argon three times, and then heated to 100 °C for 8 hours while maintaining argon protection. TLC detected that the reaction of the boronic acid raw material was complete. The reaction system was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain a light yellow oily liquid. MS (ESI) m / z : 289.93 [M + H] + .

[0096] Intermediate A-14: 5-(2-(3-methoxypropoxy)phenyl)-1 H - Preparation of pyrrole-2-carboxylic acid.

[0097] Add 2N NaOH aqueous solution (10.0 mL, 20.0 mmol) to a methanol solution (5.0 mL) of intermediate A-13 (130 mg, 0.45 mmol). Stir at 60 °C for 1.5 h and evaporate under reduced pressure. Dilute the residue with water and acidify to pH 3-4 with aqueous hydrochloric acid (3N). Extract with ethyl acetate (2×15 mL), dry the combined organic layers over anhydrous sodium sulfate, and use them in the next step without further purification after vacuum concentration.

[0098] Compound 81: 5-(2-(3-methoxypropoxy)phenyl)-N-(4-(oxazol-5-yl)phenyl)-1-(4-(oxazol-5-yl)phenyl)- H -Preparation of pyrrole-2-carboxamide.

[0099] The preparation method is similar to that of Compound 2 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s,1H), 10.11 (s, 1H), 8.41 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.81 (dd, J =7.8, 1.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.60 (s, 1H), 7.33 – 7.24 (m,1H), 7.21 – 7.11 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.77 (dd, J = 3.9, 2.5Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.58 (t, J = 6.2 Hz, 2H), 3.27 (s, 3H), 2.10 (p, J = 6.2 Hz, 2H). HRMS (m / z): calculated for C 24 H 23 N3O4 + [M+H] + 418.1689; found, 418.1683.

[0100] Example 5

[0101]

[0102] The preparation conditions of Example 5 include: I, chloromethyl trimethylsilyl ethyl ether, triethylamine, N,N-dimethylformamide, 0°C to room temperature, 8h; II, sodium hydroxide, ethanol: water, 60°C, 1.5 hours; III, 1-butyl phosphoric anhydride (T4P), N,N-dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h; IV, (2-(methoxycarbonyl)phenyl)boric acid, tetrakis(triphenylphosphine)palladium, potassium carbonate, dioxane: water (5:1), 90°C, 16h; V, trifluoroacetic acid, tetrahydrofuran, room temperature, overnight; VI, piperidine, 1-butyl phosphoric anhydride (T4P), N , N -Dimethylaminopyridine (DMAP), tetrahydrofuran, room temperature, 0.5h.

[0103] Intermediate A-15: 4-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of ethyl imidazole-2-carboxylate.

[0104] Under ice-cooling conditions, triethylamine (12.49 mL, 90 mmol) was added to 4-bromo-1 H -pyrrole-2-carboxylic acid ethyl ester (6.54 g, 30 mmol) in THF solution (20 mL), followed by dropwise addition of chloromethyl trimethylsilyl ethyl ether (SEMCl) (10.64 ml, 60 mmol). The reaction solution was then stirred at room temperature overnight. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (3 × 100 mL), washed with saturated NaHCO3 solution (2 × 100 mL), washed with saturated sodium chloride solution (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (PE: EA = 0 → 5%) to obtain colorless oily solid A-15. 1 H NMR (400MHz, DMSO- d 6) δ 7.77 (s,1H), 5.58 (s, 2H), 4.26 (t, 2 H), 3.48 (t, 2H), 1.24 (t, 3H), 0.70-0.78 (m, 2H), 0.00 (s, 9H). MS(ESI) m / z : 230.35 [M – OCH2CH2Si(CH3)3] - .

[0105] Intermediate A-16: 4-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1 H - Preparation of imidazole-2-carboxylic acid.

[0106] The preparation method is similar to that of A-2 in Example 1.

[0107] Intermediate A-17: 4-Bromo- N -(4-oxazol-5-yl)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1 H - Preparation of imidazole-2-carboxamide.

[0108] Preparation method: Intermediate A-3 in Reference Example 1. MS (ESI) m / z : 464.21 [M + H] + .

[0109] Intermediate A-18: 2-(2-(4-oxazol-5-yl)phenyl)carbamoyl)-1-(2-(3-(trimethylsilyl)ethoxy)methyl)-1 H Preparation of methyl 4-imidazol-4-yl)benzoate.

[0110] Preparation method: Refer to the intermediate A-4 in Example 1. MS (ESI) m / z : 519.33 [M + H] + .

[0111] Intermediate A-19: 2-(2-(4-oxazol-5-yl)-3-methoxyphenyl)carbamoyl)-1 H Preparation of 4-imidazol-4-yl)benzoic acid.

[0112] The preparation method is similar to that of Intermediate A-5 in Example 1.

[0113] Compound 86: N -(4-(oxazol-5-yl)phenyl)-5-(2-(piperidine-1-carbonyl)phenyl)-1 H - Preparation of imidazole-2-carboxamide.

[0114] The preparation method is similar to that of Compound 2 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 13.58 (d, J = 97.8 Hz, 1H), 10.53 (d, J = 103.7 Hz, 1H), 8.42 (d, J = 3.4 Hz, 1H), 8.12 –7.84 (m, 3H), 7.77 – 7.68 (m, 2H), 7.67 – 7.54 (m, 2H), 7.49 (td, J= 7.5,1.3 Hz, 1H), 7.42 – 7.33 (m, 1H), 7.29 – 7.12 (m, 1H), 3.79 – 3.45 (m, 2H), 3.05 – 2.83 (m, 2H), 1.49 (m, 4H), 0.84 (m, 2H). HRMS (m / z): calculated forC 25 H 23 N5O3 + [M+H] + 442.1801; found, 442.1797.

[0115] Example 6

[0116]

[0117] The preparation conditions of Example 6 include: I. p-Toluenesulfonylmethyl isocyanide, sulfonyl chloride, lithium diisopropylamide (LDA), dimethylamine hydrochloride, triethylamine, chloroform→tetrahydrofuran→tetrahydrofuran, -45°C→0°C→room temperature; II. palladium carbon / hydrogen, room temperature, 4 hours.

[0118] Intermediate B-3: N , N - Preparation of dimethyl-5-(4-nitrophenyl)oxazol-2-amine.

[0119] This is a one-pot three-step reaction. First, p-toluenesulfonylmethyl isocyanide (1.62 g, 8.32 mmol) was dissolved in chloroform, and the reaction system was placed in a low-temperature reactor at -45 °C. At -45 °C, sulfonyl chloride (0.63 mL, 8.32 mmol) dissolved in chloroform was slowly added dropwise, and the reaction was continued for 10 minutes after the addition was completed. Then it was slowly warmed to room temperature, and the system was directly heated and concentrated under reduced pressure to remove the solvent, and it could be used without additional purification. In the second step, the product of the first step was dissolved in anhydrous tetrahydrofuran in an ice-water bath at 0 °C, and then p-nitrobenzaldehyde (0.95 g, 6.93 mmol) dissolved in anhydrous tetrahydrofuran and LDA tetrahydrofuran solution (2.0 mol / L) (2.88 ml, 20.79 mmol) were added in sequence, and the reaction system was stirred continuously at room temperature for 7 hours. In the third step, a tetrahydrofuran solution of triethylamine (6 eq) and dimethylamine hydrochloride (3.39 g, 41.58 mmol) was added to the above reaction system, and then stirred for 20 hours. The reaction mixture was filtered with silica gel, and the filtrate was collected and concentrated under reduced pressure, and then purified by silica gel column chromatography with a polarity of PE:EA=1:1 to obtain a red solid B-3. 1 H NMR (400 MHz, DMSO- d 6) δ 8.18 (d,J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 1.5 Hz, 2H), 3.05 (s, 6H). MS(ESI) m / z : 234.16 [M + H] + .

[0120] Intermediate B-4: 5-(4-aminophenyl)- N , N - Preparation of dimethyloxazol-2-amine.

[0121] The preparation method is similar to that of B-2 in Example 1. 1 H NMR (400 MHz, DMSO- d 6) δ 7.16 (d, J =2.0 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 6.84 (s, 1H), 6.53 (d, J = 2.1 Hz,1H), 6.52 (d, J = 2.0 Hz, 1H), 5.17 (s, 2H), 2.94 (s, 6H). MS(ESI) m / z :204.10 [M + H] + .

[0122] Compound 89: N -(4-(2-(dimethylamino)oxazol-5-yl)phenyl)-4-(2-(piperidine-1-carbonyl)phenyl)-1 H - Preparation of imidazole-2-carboxamide.

[0123] The preparation method is based on compound 86 in Example 5. LC-MS (ESI) m / z: 485.22 [M + H] + .

[0124] Table 1 Compounds 1-102

[0125]

[0126] Evaluation of pharmacological activity of compounds

[0127] 1. In vitro enzyme level experiment.

[0128] The in vitro enzyme level test was performed using a fluorescence polarization-based method. The experimental method was briefly described as follows: First, 30 nM GST-YTHDC1 (345-509) protein was incubated with a series of small molecules to be tested at different concentrations for 30 min, and then m 6 A modified fluorescent label, m 6 A can compete with the small molecule to be tested for the binding site of YTHDC1 and incubate at 18°C ​​for 4 hours. Finally, the fluorescence polarization value of each well is read on the microplate reader and its inhibition rate is calculated. Then, Graphpad 8.0 is used to calculate its IC 50 The results are shown in Table 2.

[0129] Table 2 YTHDC1 inhibitory activity of compounds 1-102

[0130] Compound <![CDATA[IC 50 (μmol)]]> Compound <![CDATA[IC 50 (μmol)]]> Compound <![CDATA[IC 50 (μmol)]]> 1 ＞50 2 7.07 3 1.74 4 ＞50 5 31.91 6 33.24 7 ＞50 8 32.57 9 4.32 10 1.52 11 ＞50 12 2.52 13 ＞50 14 6.59 15 1.82 16 21.19 17 2.14 18 28.28 19 1.17 20 1.16 21 1.46 22 0.53 23 1.65 24 2.25 25 2.78 26 1.65 27 31.29 28 4.01 29 6.7 30 0.32 31 0.17 32 26.49 33 0.61 34 2.29 35 ＞50 36 9. 4 37 2.29 38 5.3 39 ＞50 40 0.94 41 0.53 42 1.68 43 1.18 44 4.07 45 1.14 46 5.6 47 3.9 48 0.99 49 0.67 50 1.14 51 1.03 52 0.63 53 0.59 54 5.76 55 5.74 56 4.68 57 0.248 58 0.349 59 0.256 60 0.272 61 0.27 62 4.38 63 0.053 64 0.096 65 0.126 66 0.036 67 0.04 68 0.070 69 0.035 70 0.111 71 0.032 72 0.73 73 0.85 74 ＞50 75 0.829 76 2.19 77 ＞50 78 2.1 79 ＞50 80 2.5 81 ＞50 82 ＞50 83 ＞50 84 ＞50 85 2.56 86 0.08 87 0.14 88 0.322 89 0.07 90 0.164 91 0.038 92 0.215 93 0.046 94 0.03 95 0.017 96 0.141 97 0.129 98 0.078 99 0.075 100 0.096 101 0.069 102 2.87

[0131] Combined with the co-crystal structure of the interaction between YTHDC1 and small molecules and the data in Table 2, the structure-activity relationship of the compounds of the present invention is summarized as follows.

[0132] (1) The five-membered nitrogen heterocycle is the structural core of the series of compounds of the present invention. The carbonyl group (C=O) and NH bond of the amide bond form key hydrogen bond interactions with the NH on the indole ring of tryptophan at position 377 and the -COOH of aspartic acid at position 476, respectively, forming the basis of activity. At the same time, the exposed NH adjacent to the amide bond on the five-membered nitrogen heterocycle is essential for activity. When the NH faces the inside of the pocket, it can form a hydrogen bond interaction with the C=O of serine at position 378; when the NH faces the outside of the pocket, it can also form a hydrogen bond interaction with the -COOH of aspartic acid at position 476. Therefore, the pyrrole rings in both directions are active. After the pyrrole is modified to imidazole, the imidazole ring that can form a bidirectional hydrogen bond generally has higher activity.

[0133]

[0134] (2) The volume of the R1 group has a great influence on the activity. A larger R1 group can form a larger dihedral angle between the five-membered nitrogen heterocyclic ring and the benzene ring through steric hindrance, thereby allowing the benzene ring to extend into the hydrophobic aromatic cage pocket formed by tryptophan at position 377, tryptophan at position 428, leucine at position 430, and leucine at position 439, forming an important π-π stacking effect. For example, when the volume size relationship of the R1 group is benzoic acid condensation with secondary amine > benzoic acid condensation with primary amine > aniline condensation with carboxylic acid, the activity relationship is also consistent with the volume relationship; when R1 is a smaller group or a long chain group (such as compound 81), due to its small volume, the benzene ring cannot flip into the aromatic cage, so the activity is poor.

[0135] (3) When a substituent is introduced on the other side of the benzene ring directly connected to the five-membered nitrogen heterocyclic ring to form a di-ortho-substituted aromatic group, although the dihedral angle can be increased in theory, causing the benzene ring to flip and enter the aromatic cage (e.g. compounds 79 and 83), the activity is significantly reduced. This may be because the other side group extends to the inside of the pocket, and the increased volume makes it easy to collide with the amino acid inside the pocket, thus weakening the activity. However, some compounds with di-ortho-substituted aromatic groups (e.g. compound 85) still have good activity.

[0136] (4) The rightmost oxazole ring forms a parallel stacking π-π interaction with the phenylalanine at position 358. The introduction of an electron-donating group can enhance this interaction, with the best activity being achieved after the introduction of a dimethylamine group (for example, the activity of compound 66 is nearly 10 times higher than that of compound 22).

[0137] In summary, the present invention designs a five-membered nitrogen heterocyclic amide structure substituted with an aromatic group having a bulky substituent, so that the compound of the present invention has excellent inhibitory activity against YTHDC1; at the same time, the five-membered nitrogen heterocyclic ring and oxazole substituents are further optimized to further improve the activity of the compound.

[0138] 2. In vitro cell experiments.

[0139] Main instruments: biological safety cabinet, CO2 cell culture incubator, flow cytometer, fluorescence inverted microscope, multifunctional microplate reader, precision electronic balance.

[0140] Main consumables: cell culture dishes, 12-well plates, 96-well plates, 384-well plates.

[0141] Main reagents: 1640 complete culture medium, fetal bovine serum (Hyclone, South America), penicillin-streptomycin double antibody solution. Cell cycle and apoptosis kit, PE-CD11b and APC-CD14 flow cytometry antibodies, MTT powder, SDS powder. Positive control YL-5092.

[0142]

[0143] Cell line: Acute myeloid leukemia cells (MOLM-13).

[0144] MTT assay for cell proliferation: AML cells (MOLM-13) were plated in 96-well plates at 10,000-15,000 cells per well, and then a series of concentration gradients of 66, 69, 71, and YL-5092 (positive control, IC 50 =0.011 nm) for 72 h, 20 μL MTT solution (5 mg / L) was added to each well and incubated for 2-4 h, and then 50 μL 20% SDS solution was added to each well and incubated overnight to dissolve the formazan. The absorbance was then read at 570 nm on a microplate reader and the IC values ​​of 66, 69, 71, and YL-5092 were calculated using GraphPad Prism 8.0. 50 The result is Figure 1 shown.

[0145] Depend on Figure 1 It can be seen that compounds 66, 69, and 71 of the present invention can inhibit the proliferation of AML cells (MOLM-13), IC 50 The values ​​ranged from 2.196, 3.147, and 2.226 μM, respectively, and the positive control YL-5092 was 1.739 μM. This indicates that the compound of the present invention can inhibit the growth of acute myeloid leukemia tumor cells, and can be used as a YTHDC1 inhibitor, providing a new option for the development of anti-AML drugs. At the same time, the anti-MOLM-13 activity and the YTHDC1 enzyme level inhibitory activity show a strong correlation, providing experimental data support for the development of more active and better drug-forming YTHDC1 small molecule inhibitors.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that: The structure of Formula I is as follows: in, X1 is NH, X2 is CH, and X3 is CH; or, X1 is NH, X2 is N, and X3 is CH; R1 is selected from: R2 is selected from hydrogen or -N(R 2a )2; R 2a Selected from C 1～4 Alkyl or C 1～4 Deuterated alkyl; R3 is selected from hydrogen; R4 is selected from hydrogen, substituted or unsubstituted C 1～4 Alkoxy; In R4, the substituted C 1～4 The substituents of the alkoxy group are selected from deuterium.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2a Selected from C 1～2 Alkyl or C 1～2 Deuterated alkyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R2 is selected from hydrogen, 4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R4 is selected from hydrogen, methoxy, deuterated methoxy, ethoxy or deuterated ethoxy.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound is selected from:

6. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

7. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and is supplemented with pharmaceutically acceptable auxiliary ingredients.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 7 in the preparation of a YTHDC1 small molecule inhibitor.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing leukemia.

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